Critical Review of Diagnostic Methods Used in Chronic Pancreatic Disease

REVIEW

Critical review of diagnostic methods used in chronic pancreatic disease

IVAN TBECK MD PHD FRCPC FACP FACG

HIS REVIEW DEALS WITH THE IT BECK. Critical review of diagnostic methods used in chronic pancreatic disease. Can J Gastroenterol 1995;9(1):51-60. This paper provides a balanced assessment of the vari- T diagnostic modalities used to in- ous pancreatic function tests and imaging techniques used in the differential diagnosis of vestigate chronic pancreatic disease chronic pancreatic disease. Function tests that study the digestive capacity of the pancreas and the methods employed to differen- (fat absorption of dietary lipids, fluorescein- or radiolabelled fats, bentiromide test, etc) tiate chronic pancreatitis from carci- have high specificity, but very low sensitivity. This is because 90% of pancreas has to be noma of the pancreas. Other destroyed before steatorrhea or creatorrhea occurs. Tests that directly measure pancreatic conditions that lead to pancreatic in- bicarbonate and protein secretion (secretin test, etc) are more accurate and may detect sufficiency without pancreatitis or can- pancreatic dysfunction even before anatomical changes occur. Measurement of pancre- cer (such as cystic fibrosis, primary atic enzymes in serum or urine, or the decreased decline of serum amino acids during their pancreatic atrophy of childhood, adult incorporation into pancreatic enzymes, are not sufficiently sensitive or specific to help di- pancreatic lipomatosis or isolated agnose pancreatic disease. Sensitive and specific tumour markers are not yet available. lipase-colipase deficiency, etc) will not Thus screening tests are not cost-effective – if they are negative, they do not exclude pancreatic disease; and if positive, they have to be confirmed by more specific tests. Imaging be discussed although these conditions techniques are the most commonly used methods of investigation. The usefulness of ab- may also lead to abnormal pancreatic dominal survey films, barium studies, percutaneous transhepatic cholangiography, endo- function tests. The subject of the pres- scopic retrograde cholangiopancreatography (ERCP), ultrasonography, computed ent paper was reviewed in more detail tomographic scan, magnetic resonance imaging and endoscopic ultrasonography is criti- by the author two years ago (1). The cally reviewed. Most of the radiological methods can be combined with cytology or biopsy. present paper is a more general over- Histology demonstrating malignancy establishes this diagnosis, but negative biopsies do view and a critical assessment of the not exclude malignant tumours. Presently only ERCP and endoscopic ultrasound can diag- methods used and an update on recent nose cancers sufficiently early to allow for possible ‘curative’ surgery, and only endoscopic developments. ultrasound is capable to stage tumours for the assessment of resectability. The clinical features of chronic pan- Key Words: Computed tomographic scan, Endoscopic retrograde cholangiopancreatography, creatitis and carcinoma are shown in Endoscopic ultrasonography, Imaging techniques, Pancreatic biopsies, Pancreatic function tests, Figures 1 and 2. The common denomi- Secretin test, Tumour markers nator of both diseases is replacement of functioning parenchyma and the duct Analyse critique des méthodes diagnostiques utilisées dans la system with nonfunctioning tissue: in- pancréatite chronique flammatory tissue and fibrosis in RÉSUMÉ : Cet article présente une évaluation équilibrée des diverses épreuves de fonc- chronic pancreatitis, and tumour in tion du pancréas et des techniques d’imagerie utilisées pour le diagnostic différentiel de la cancer of the pancreas. The clinical pancréatite chronique. Les épreuves de fonction qui portent sur la capacité digestive du symptoms, biochemical abnormalities pancréas (absorption des graisses d’origine alimentaire, fluorescéine ou graisses radio- and anatomical distortions in both marquées, épreuve au bentiromide, etc.) s’accompagnent d’un degré élevé de spécificité, conditions are due to ductal obstruc- mais d’une très faible sensibilité. Cela est dû au fait que 90 % du pancréas doit être détruit tion, diminished parenchymal or avant que ne survienne la stéatorrhée ou la créatorrhée. Les épreuves qui visent une me- ductal-cell function and the presence sure directe des bicarbonates du pancréas et la sécrétion protéique (test de la sécrétine, of mass lesions. Except in the case of voir page suivante functioning islet cell tumours (which Queen’s University, Kingston, Ontario are not the subject of this review), dif- Correspondence and reprints: Dr IT Beck, Division of Gastroenterology, Department of ferentiation between the two condi- Medicine, Hotel Dieu Hospital, Queen’s University, Kingston, Ontario K7L 5G2 tions may be very difficult (1-3). As Received for publication April 5, 1994. Accepted June 13, 1994 shown in Figures 3 and 4, cystic and

CAN JGASTROENTEROL VOL 9NO 1JANUARY/FEBRUARY 1995 51 BECK

LABORATORY TESTS etc.) sont plus précises et peuvent déceler une dysfonction pancréatique avant même que ne surviennent des changements anatomiques. La mesure des enzymes pancréatiques séri- (TABLE 1) ques ou urinaires ou l’atténuation de la baisse des amino-acides sériques durant leur incor- Pancreatic function tests poration aux enzymes pancréatiques ne sont pas suffisamment sensibles ni précises pour contribuer au diagnostic de la pancréatite. Les marqueurs tumoraux sensibles et spéci- Tests that assess digestive capacity of fiques se font encore attendre. Donc, les épreuves de dépistage ne sont pas économiques; si the pancreas (Table 2): Tests based on elles sont négatives, elles permettent d’exclure une maladie pancréatique; si elles sont measuring the digestive capacity of the positives, elles doivent encore être confirmées à l’aide d’autres tests plus spécifiques. Les pancreas are less sensitive than those techniques d’imagerie sont les méthodes d’investigation les plus fréquemment utilisées. that directly measure pancreatic secre- L’utilité des plaques simples de l’abdomen, des épreuves barytées, de la cholangiographie tion. This is because the normal pan- transhépatique percutanée, de la cholangiopancréatographie endoscopique rétrograde creas has considerable reserve capacity, (CPER), l’échographie, la scintigraphie, l’imagerie par résonnance magnétique et l’écho- and steatorrhea and creatorrhea be- graphie endoscopique sont passées en revue. La plupart des méthodes radiologiques peuvent être combinées à la cytologie ou à la biopsie. L’histologie permet d’établir un come biochemically detectable only diagnostic de néoplasie le cas échéant, mais les biopsies négatives ne permettent pas d’ex- when lipase and trypsin secretion has clure les tumeurs malignes. À l’heure actuelle, seule la CPER et l’échographie endoscopique been reduced to less than 10% of nor- peuvent diagnostiquer les cancers suffisamment tôt pour permettre une chirurgie curative mal (5), and steatorrhea may not be de- possible et seule l’échographie endoscopique peut déterminer si la chirurgie est faisable. tectable until 75% of the pancreas has been resected. Thus, fecal fat studies are insensitive in mild chronic pancreatic disease. Fecal fat balance study: Steatorrhea occurs due to maldigestion (pancreatic disease) and to malabsorption (as a re- sult of many other conditions, including intestinal disease). Differentiation between the two can be achieved by the method described below. Fecal fat balance study before and during pancreatic replacement therapy: Steatorrhea due to pancreatic disease is diagnosed if fat absorption im- proves with oral ingestion of pancreatic enzymes. Gastric acid may lower duodenal pH below the level that is opti- mal for lipase activity, and the simultaneous administration of enzymes and a H2 receptor antagonist Figure 1) Clinical and biochemical features caused by the anatomical changes of chronic pancreati- may further improve fat absorption tis. Reproduced with permission from reference 1 (6). Colipase, a factor needed for appro- solid tumours can occur in chronic demonstrate abnormal pancreatic priate lipase activity, plays an impor- pancreatitis as well as in benign and function (pancreatic function tests) tant role in fat digestion, and steator- malignant neoplasms (4). Further- and immunoassays for tumour markers rhea may occur in congenital isolated more, calcification can occur in to differentiate between benign and lipase-colipase deficiency (7). chronic pancreatitis and in several of malignant disease. The second cate- Screening tests for pancreatic maldi- the benign or malignant tumours. In gory consists of imaging and biopsy gestion: These tests, which study fat, addition, chronic pancreatitis is a risk techniques used to establish the ana- starch or peptide digestion, have been factor for pancreatic cancer (2,3). tomical basis for abnormal function. developed to simplify the cumbersome Once the suspicion of pancreatic Recent imaging techniques have re- fecal fat balance study. Most of them disease has been raised on clinical placed, to a great extent, the pancreatic are less sensitive and specific than the grounds, investigation is warranted to function tests, but evaluation and un- 72 h fecal fat excretion. determine whether chronic pancreatic derstanding of the usefulness of indi- Macroscopic and microscopic examination disease is present, and if so, whether vidual tests is important in the of stool: Considering the low sensitiv- this is chronic pancreatitis or carci- investigation of patients with malab- ity of the balanced chemical fecal fat noma. The methods employed can be sorption syndrome and in the differen- determination, one would expect that divided into two major categories. The tiation of pancreatic maldigestion from the qualitative (microscopic) exami- first consists of laboratory tests used to malabsorption due to other causes. nation of stool is devoid of sensitivity,

52 CAN JGASTROENTEROL VOL 9NO 1JANUARY/FEBRUARY 1995 Review of diagnostic methods for chronic pancreatitis

Figure 2) Chemical and biochemical features caused by the anatomical and hormonal alterations of cancer of the pancreas. Reproduced with permission from reference 1 and thus may lead to diagnostic confu- sion. Pancreolauryl test: This pancreatic function test is based on the digestion of di- dodecanoic ester of fluorescein by pancreatic lipase. Because 90% of lipase activity has to be destroyed before even the accurate 72 h fecal fat balance study becomes abnormal, it is not astonishing that the sensitivity of the pancreolauryl test (which is based on a single dose of administered fluorescein fat) is low (8). The sensitivity of the test was reported in severe pancreatic disease to be be- Figure 3) Classification of benign tumours of the pancreas tween 80 and 90% but it is much lower in mild chronic pancreatitis (1). Bentiromide test: This test is based on the digestion of benzoyl-L tyrosil- L-p-aminobenzoic acid (NBT-PABA). Because the tyrosil-p-aminobenzoic acid bond is specific for chymotrypsin, this synthetic peptide is digested only by chymotrypsin. The hydrolysis of this peptide results in the release of p-aminobenzoic acid, which is absorbed and ex- creted in urine. As this test is based on intraduodenal digestion by chymotrypsin, which is present in the pancreas in great excess, the test becomes positive only in patients with severe pancreatic insufficiency (8,9). Other screening tests for pancreatic maldigestion: The 14C triolein and fatty Figure 4) Classification of malignant tumours of the pancreas BECK

TABLE 1 and carbohydrate digestion, the 14C fat min E levels and the vitamin E:total Laboratory tests used to investigate absorption tests become positive only plasma lipid ratio are abnormally low in chronic pancreatic disease in patients with severe pancreatic in- 75% of patients with chronic alcoholic Pancreatic function tests designed to sufficiency (1,2). pancreatitis and in 91% of those with assess: Vitamin B12 absorption depends on steatorrhea. Although it has been sug- Digestive capacity of the pancreas splitting the R protein from cobalamin gested that this determination may be a Pancreatic synthetic and exocrine by pancreatic enzymes. The Schilling practical means of detecting steator- secretory function test may be abnormal in some patients rhea in patients with alcoholic chronic Pancreatic endocrine function with severe pancreatic insufficiency; pancreatitis (11), fecal fat balance still Tests designed to differentiate between chronic pancreatitis and cancer vitamin B12 blood levels usually remain remains the standard for abnormal fat Modified from reference 1 normal (10). excretion. Low folate levels, if present, Other tests of malabsorption: Clini- are usually related to excessive alcohol cally significant malabsorption of pro- consumption rather than pancreatic in- teins and fat-soluble vitamins occurs sufficiency. acid absorption and breath tests (the only rarely in chronic pancreatic dis- Differentiation of malabsorption first depends on duodenal lipase activ- ease. Thus, serum albumin is usually from pancreatic maldigestion can be ity and the second on intestinal absorp- normal, and carotene (for vitamin A), achieved by tests that depend on intes- tion) have been used to differentiate serum calcium, phosphate and alkaline tinal absorption rather than digestion. between maldigestion and malabsorp- phosphatase (for vitamin D) and Thus, the xylose absorption test and tion. However, similar to the nonra- prothrombin time (for vitamin K) are lactose tolerance tests are normal in 13 dioactive C-CO2 breath test for fat usually normal. However, plasma vita- pancreatic insufficiency. Tests of pancreatic exocrine secretory TABLE 2 and synthetic function (Table 3): Tests designed to investigate the digestive capability of the pancreas Tests in this category are based on the Fecal fat excretion (does not differentiate between pancreatic and other types of secretory and synthetic function of the malabsorption) pancreas. Assessment of this function Fecal fat excretion before and during pancreatic replacement therapy can be done either by directly deter- Screening tests mining the composition of pancreatic Macroscopic and microscopic examination of stool secretion obtained by peroral intuba- 14 Starch digestion test for amylase (hydrogen, C-CO2 breath test) tion, or by deducing secretory functions 131 I-triolein and fatty acid digestion and absorption test (blood and urine) from the concentration of enzymes or 14 14 C-triolein and fatty acid digestion and absorption test ( C-CO2 breath test) their substrate in blood, urine or stool. 13 13 1,3 distearyl-2 carboxyl- C octanoyl glyceryl test for digestion by lipase ( C-CO2 Tests requiring duodenal intubation: breath test) Stimulation of pancreatic secretions Fluorescein dilauryl test for digestion by lipase can be achieved either by parenterally N-benzoyl-L-tyrosyl-L-p-aminobenzoic acid (NBT-PABA) urinary excretion test administered hormones or by stimulat- Other tests of malabsorption that may be positive in chronic pancreatitis ing the pancreatic secretions with in- Low serum protein Malabsorption of fat-soluble vitamins traduodenally administered food. Vitamin A: Low serum carotene Direct stimulation of the pancreas with Vitamin D: Low serum calcium, elevated alkaline phosphatase parenterally administered hormones: The Vitamin K: Prolonged prothrombin time first changes of chronic pancreatitis occur in the ductal cells. Because B12 absorption (Schilling test and double-labelled Schilling test) secretin-stimulated bicarbonate secre- Modified from reference 1 tion depends on ductal function, the most accurate method to assess pancre- TABLE 3 atic function is the intraduodenal Tests designed to study pancreatic synthetic and exocrine secretory function measurement of the secretin- Tests requiring duodenal intubation (‘invasive’) stimulated pancreatic bicarbonate se- Direct stimulation with secretin, cholecystokinin, caerulein, bombesin cretion. Based on over 5000 cases the Indirect stimulation: Lundh test meal, fatty acid or amino acid test meals sensitivity of the tests was 90% and the Tests not requiring duodenal intubation (‘noninvasive’) specificity was 94%. False positive re- Fecal enzyme determination: chymotrypsin sults occurred in patients with va- Serum or plasma levels (with or without provocative testing) of: gotomy, gastric surgery, diabetes and Substances required in synthetic activity: amino acids inaccurate tube placement (12). ‘False Substances synthesized: pancreatic amylase, trypsinogen, lipase, pancreatic positive’ results may not necessarily be polypeptide falsely positive. Abnormal pancreatic Modified from reference 1 function after vagotomy or gastric sur-

54 CAN JGASTROENTEROL VOL 9NO 1JANUARY/FEBRUARY 1995 Review of diagnostic methods for chronic pancreatitis gery may relate to abnormal neuroen- with celiac disease. Tests based on duo- not require laparotomy or biopsy. Se- docrine control of pancreatic secre- denal perfusion with fatty acids or rum and duodenal tumour markers ini- tions. Evidence is accumulating that a amino acids have the same limitations. tially appeared the most promising; high proportion of insulin-dependent Tests that do not require duodenal in- however, many of the proposed tests, diabetics may have exocrine pancreatic tubation: Because ‘invasive tests’ are such as carcinoembryonic antigen dysfunction, including ductular abnor- difficult to perform and some patients (CEA), pancreatic oncofetal antigen malities (13). Hypersecretion was ob- resist prolonged nasoduodenal intuba- and ribonuclease, are not sufficiently served in patients with cirrhosis. False tion, investigators have attempted to sensitive to provide a differential diag- negatives were mainly due to inaccu- develop sensitive and specific tests that nosis (17). rate tube placement, which can be can be performed without intubation. More promising are the carbohy- avoided by careful fluoroscopy (12). Fecal chymotrypsin: The overall prote- drate antigens, especially CA 19-9, the The secretin test becomes positive be- olytic activity in feces reflects the ac- marker that has the closest association fore any other function test, and an ab- tivities of a mixture of bacterial, pan- with pancreatic cancer (17,18). It has normal secretin test precedes the earli- creatic and other peptidases. Therefore, been reported that this carbohydrate est structural abnormalities that can be a method using specific substances for antigen has a sensitivity of 78% in re- demonstrated by endoscopic retrograde fecal chymotrypsin activity is more spe- sectable and 91% in unresectable pan- pancreatography (14). cific. Unfortunately, fecal chymotryp- creatic cancer. The specificity of the The hormones cholecystokinin sin becomes abnormal only in ad- test is 92%. Unfortunately, the test has (CCK), caerulein and bombesin stimu- vanced pancreatic disease (1,2). a relatively low sensitivity in early de- late enzyme secretion by alveolar cells. Serum or plasma amino acids: During tectable lesions, so it cannot be used as Diminished hormone stimulated in- amino acid incorporation into newly a screening test. The antigen was origi- traduodenal enzyme concentration oc- synthesized pancreatic protein, a fall in nally extracted from a colon cancer, is curs early in pancreatic insufficiency. plasma amino acid levels occurs after positive, and is expressed in cancers of These tests, however, have not been as secretin and pancreozymin stimulation. the colon (19) and other gastrointesti- well standardized as the secretin test Slowing of the rate of plasma amino nal carcinomas. The monoclonal anti- (12). acid decrease may suggest exocrine body is expensive, and the test does not Other ‘invasive’ tests requiring duo- pancreatic insufficiency. Unfortu- appear to be cost-effective at present. denal intubation have been proposed. nately, overlaps occur between normal For instance, the above-mentioned patients and those with pancreatic dis- METHODS TO DETERMINE hormones increase secretion of calcium eases (1,16). THE ANATOMICAL BASIS FOR and lactoferrin, and abnormally high Serum and urine levels of pancreatic en- ABNORMAL FUNCTION concentrations can be measured in zymes: Serum and urinary isoamylase Imaging techniques (Table 4) duodenal juice of patients with early and lipase are useful in the diagnosis of chronic pancreatitis. However, duode- acute pancreatitis. However, these en- Indirect radiological methods: Con- nal lactoferrin levels are also elevated zymes are of no help in the diagnosis of ventional x-ray techniques cannot dif- in patients with duodenitis (1,2). A chronic pancreatitis or pancreatic neo- ferentiate between the densities of pancreatic function test was developed plasm, except during an acute relapse or pancreatic and peripancreatic tissues. incorporating 75Se methionine into the presence of pseudocysts where these Therefore, except when the pancreas is pancreatic proteins. Increased 75Se enzymes may remain elevated during calcified, the abdominal survey film methionine labelled protein excretion the active presence of a pseudocyst. does not show the pancreas. Attempts into the duodenal juice has been re- Tests assessing endocrine pancreatic to visualize pancreatic anatomy directly ported to occur in early chronic pan- function: Frank diabetes does not oc- by isotope scanning techniques (75Se creatitis, but this observation has not cur in chronic pancreatic disease until methionine) do not provide images yet been confirmed (1,2). approximately 90% of the islets have that could accurately differentiate nor- Indirect stimulation tests: The indirect been destroyed. Therefore, demonstra- mal from diseased pancreas. Therefore, test described by Lundh (15) measures tion of carbohydrate intolerance is not before the existance of ultrasound and the secretory response to an intraduo- helpful for the early diagnosis of pancre- computed tomography (CT) scan, di- denally administered liquid test meal. atic disease. Both insulin and glucose rect visualization of the pancreas was Diminished enzyme secretion in re- levels vary considerably in patients not possible. Up to the late 1970s, ra- sponse to the test meal occurs in pan- with chronic pancreatitis, and their diological diagnosis of pancreatic dis- creatic insufficiency. However, indirect levels do not provide useful informa- ease depended entirely on ‘indirect pancreatic secretory stimulation de- tion (2). methods’. These were based on detec- pends on the release of secretin and CCK tion of distortion, compression or in- Tumour markers for differentiating from the duodenal mucosa, which may vasion by benign or malignant masses cancer from chronic pancreatitis be impaired in patients with duodenal of hollow organs (stomach, duodenum, mucosal abnormalities. False positive Many attempts have been made to colon), ducts (pancreatic or common results have been reported in patients develop diagnostic techniques that do BECK

TABLE 4 TABLE 5 malignancy causes jaundice with Imaging techniques Ultrasonic and computerized tomo- symptoms, palliative treatment with graphic scan of chronic pancreatitis (CP) stenting is safer and less invasive than Indirect and cancer Barium meal surgical bypass procedures. Newer Barium enema CP Cancer stents allow for less frequent clogging Angiography Mass + +++ of the insert (21). However, the use- Percutaneous transhepatic Inhomogeneity + + fulness of pancreatic stone removal cholangiography Cystic lesions +++ + and dilation of the duct remains to be Endoscopic retrograde Calcification + + proven. cholangiopancreatography Abnormal common duct + + As some of the features of chronic Direct Abnormal pancreatic duct pancreatitis and pancreatic cancer are Abdominal survey film (if calcified) Smooth dilation + +++ similar, differential diagnosis between Ultrasonography Beaded dilation + +++ the two may not always be easy. The Computerized tomography (CT) scan Irregular dilation +++ + most important diagnostic features are CT scan with dynamic scanning +Rare; ++Common; +++Frequent the changes that occur in the duct sys- Magnetic resonance imaging Endoscopic ultrasonography tem. The pancreatic duct of normal subjects is regular, with terminal ta- pering. Multiple irregularities of the major and secondary pancreatic ducts duct) or blood vessels filled with con- the advantage of ERCP over PTC is that are usually diagnostic of chronic pan- trast material. ERCP provides the opportunity for creatitis, and dilated ducts due to par- Barium meal and barium enema: Bar- therapeutic intervention, with sphinc- tially obstructive tumour are sharply ium studies of the stomach and duode- terotomy or stenting in the same sit- delineated and have a smooth contour. num may demonstrate deformities of ting. Furthermore, for pancreatic dis- However, as these smoothly dilated the posterior wall of the stomach, and ease, ERCP is superior because it allows ducts may take on a ‘bead-like’ appear- of the bulbar, postbulbar and peripapil- for direct visualization not only of the ance, the ductal changes caused by lary regions of the duodenum. Differen- common bile duct, but also of the pan- cancer or chronic pancreatitis may tiation between cancer and chronic creatic duct. sometimes be difficult to distinguish. pancreatitis is difficult. Occasionally, ERCP: ERCP plays a principal role in The diagnosis becomes easier if the large pseudocysts or tumours may com- the overall investigation of pancreatic ductal changes of chronic pancreatitis press or invade the colon, resulting in disease. The main indications for ERCP occur in the absence of a localized ob- abnormalities of the barium enema. are to: differentiate between chronic struction. According to several studies, Angiography: Ultrasonography and CT pancreatitis and carcinoma in patients the accuracy of ERCP in differentiating scanning have, for all practical pur- with abnormal CT scan or ultrasound; benign from malignant changes is be- poses, replaced angiography in the diag- differentiate between hepatobiliary and tween 62 and 92%. The higher diagnosis of pancreatic disease. pancreatic diseases in patients with ob- nostic accuracy (92%) reported in Percutaneous transhepatic cholangi- structive jaundice; assess ductal anat- 1987 than in previous years may be re- ography: Chronic pancreatic disease omy preoperatively in patients with lated to improved technique and more may distort or obstruct the transpancre- chronic pancreatitis; prove or disprove accurate interpretation of radiological atic portion of the common bile duct. the presence of pancreatic disease in pa- images (22). Injection of dye into the intrahepatic tients in whom, based on history and Direct visualization of the pancreas – duct system via the percutaneous route function tests, there is a high degree of Abdominal survey film: This examina- provides excellent visualization of the suspicion of pancreatic disease but tion is useful as an indirect method to common duct. The method is relatively whose ultrasound and CT scans are nor- diagnose acute pancreatitis. The usual safe, the complication rate due to sepsis, mal (21). findings are localized ileus (sentinel bile leak and bleeding is around 3%, The major recent advances are in loop) or the cut-off sign of the colon. and the mortality is less than 0.2%. Un- the therapeutic applications of this Routine films cannot distinguish the til the introduction of endoscopic ret- technique. The classic indication for pancreas from surrounding soft tissues. rograde cholangiopancreatography papillotomy is the presence of common However, once calcification occurs, di- (ERCP), percutaneous transhepatic bile duct stones. Recently, sphincter of rect visualization becomes possible. cholangiography (PTC) was the method Oddi spasm has been recognized as a Calcium may be localized in a single of choice for investigating patients with possible cause of recurrent abdominal area or extend throughout the organ. obstructive jaundice (20). Since ERCP is pain and pancreatitis. It has been sug- As to the differential diagnostic value now becoming increasingly available in gested that if sphincter of Oddi motility of calcification, calcium deposits occur primary and secondary care hospitals, study is abnormal, symptoms may be re- most frequently in chronic pancreatitis; the use of PTC has been relegated to pa- lieved or relapsing pancreatitis allevi- however, they may also be present in tients in whom ERCP has failed. Clearly, ated by sphincterotomy. If a the walls of pseudocysts, cystic neo-

56 CAN JGASTROENTEROL VOL 9NO 1JANUARY/FEBRUARY 1995 Review of diagnostic methods for chronic pancreatitis plasms and in the parenchyma of carci- TABLE 6 nomas. Cystic tumours Ultrasonography: Echographic diag- Ultrasound/computed to- Endoscopic retrograde nosis of both chronic pancreatitis and mographic scan cholangiopancreatography pancreatic carcinoma is dependent on Pseudo cyst changes in size and contour of the Simple –Single –Communicates (70%) –Homogeneous gland, echoreflectivity of the paren- Complicated –Hemorrhage chyma and alteration of ductal anat- –Multiloculated omy (Table 5). Unfortunately, the –May calcify shape, size and position of the organ Serous cystadenoma –Lobulated, large –Does not communicate may differ from one normal individual (microcystic –Multiple small cysts –Draped to another, and echoreflectivity in- cystaden) –’Sunburst’ calcification Mucinous cystadeno CA –Large cysts –Does not communicate creases with age. In chronic pancreati- (macrocystic –Thick fluid –Draped tis, changes in gland size are not always cystaden CA) –Dystrophic calcification –Obstructed diagnostic because this condition may Mucinous ductal ectasia –Tumour in duct –Communicates cause pancreatic atrophy or enlarge- –Cystic dilation of duct –Thick fluid, draped ment. Alterations of contour may be –Cystic dilation of duct difficult, because the age-dependent in- Papillary cystic tumour –Tumour in duct –Obstruction –Obstruction –Draped creases in echogenicity of the gland –May cause acute –Cystic dilation of duct may render delineation of the pancreas pancreatitis –Possible pseudocyst from peripancreatic fibrous tissue diffi- Based on reference 4 cult. A solid pancreatic mass of a tumour cannot always be differentiated from that of a focal mass caused by inflammation. Also, cystic tumours may immediately after the intravenous Magnetic resonance imaging: Exami- be difficult to differentiate from pseu- injection of the bolus, cuts are made nation of the pancreas with magnetic docysts. at 1 cm intervals with a rapid scan se- resonance imaging (MRI) has been lim- Interpretation of ultrasonographic quence of less than 2 s. This allows as- ited due to distortion by respiratory mo- changes in the ducts are subject to the sessment of the relationship of a mass tion and difficulty in distinguishing same limitations were described for the to the surrounding vasculature, and de- between the bowel and pancreas. The ductal characteristics observed in ERCP. tects invasion of arteries or veins, in- head and body can be seen reasonably In a retrospective analysis of 27 pa- farctions and perfusion defects. A well, but the tail is often not visualized. tients with proven chronic pancreati- correct diagnosis of pancreatic cancer At present, the diagnostic capability of tis, similar ductal abnormalities were has been reported in 91% of 174 pa- the CT scan is superior to that of MRI found in patients with or without pan- tients with a frequency of false positive (26). creatic insufficiency, and in 13% of pa- and false negative results of 8 and 1%, A recent report indicates that MRI tients with chronic pancreatitis the respectively. Unfortunately, the accu- can noninvasively visualize the biliary ultrasound was normal (23). racy of this method was studied in pa- tract by subjecting the images obtained Computerized axial tomography: tients with advanced cancer, and only in the axial plane to a computer gener- Computerized axial tomography (CAT) six of the 174 patients had resectable ated projection of the cholangiogram is one of the most accurate direct meth- disease. Thus, even this improvement in a coronal plane. With today’s tech- ods to assess the pancreas. However, for in diagnosis using CAT scanning does not niques, the images are not as clear as the same reasons as described for ultra- allow for the early diagnosis of resecta- with invasive visualization of the ducts, sound, except for the classic examples ble cancer (25). Of special diagnostic and several episodes of 17 to 20 s breath of each disease, the differential diagno- interest are benign and malignant cys- holding are necessary to obtain an im- sis of chronic pancreatitis from carci- tic lesions of the pancreas (Figures 3,4); age (27). noma may be difficult and not always their x-ray characteristics are reviewed Endoscopic ultrasonography: Endo- possible (Table 5). Mass lesions may be in Table 6. Combined with ERCP, some scopic ultrasonography involves the at- caused by inflammation or tumour, cys- of these tumours are easily recognizable tachment of an ultrasound transducer tic changes may be due to pseudocysts and may have characteristic appear- to the endoscope. The scope is intro- or cystic neoplasia, and changes in duc- ance such as classic pseudocyst of duced into the duodenum or into the tal anatomy in chronic pancreatitis chronic pancreatitis (Figure 5), the posterior wall of the stomach. Under di- may resemble those seen in carcinoma sunburst calcification of the frequently rect endoscopic observation an echo- of the pancreas (24). benign serous cystadenomas (Figure 6) gram of the pancreas is created, which is Dynamic scanning (25) employs and the large thick fluid-filled cysts of well seen because it appears adjacent to rapid intravenous injection of 150 mL mucinous cystadeno carcinomas (Fig- the endoscopic image. Echograms of of iodinated contrast material. Starting ure 7). the relation of the pancreas to the bili- BECK

Figure 7) Computed tomographic scan of mucinous cystadeno carcinoma. Note the multiloculated fluid-filled large cysts

Top left Figure 5) Computed tomographic scan of two large pseudocysts of the pancreas. Note the sharply delineated outline of the cysts

Bottom left Figure 6) Computed tomographic scan of a serous cystadenoma. Note the ‘sunburst’ calcification within the cyst

TABLE 7 tations. Cytology from duodenal juice Methods to obtain material for histology has a very low yield of cells. Cytology Cytology from duodenal juice obtained by cannulation of the pancre- Cytology from pancreas obtained during endoscopic retrograde atic duct during ERCP is cumbersome. cholangiopancreatography by collection during secretin stimulation brushing A cytology brush or the recently devel- Cytology by ultrasonography or computed tomographic scan guided thin needle biopsy oped biopsy forceps can be introduced Cytology obtained during endoscopic ultrasonography easily into the head of the pancreas Biopsy obtained during endoscopic retrograde cholangiopancreatography during ERCP. However, obtaining Biopsy obtained during surgery specimens from other parts of the gland may be difficult and often impossible (30). The major disadvantage of the ul- ary system, portal vein, arteries and the a tumour. However, by now endoscopic trasound or CT scan thin needle biopsy aorta can be obtained. Differentiation ultrasonography has proven to be the is that it may be difficult to differenti- of malignant and benign tumours of the best method to assess peripancreatic lo- ate tumour mass from pericancerous pancreas is possible for masses of 30 mm cal invasion and help to decide preop- edema on the scan. If the latter is biop- diameter, and even as small as 20 mm. It eratively on resectability of the tumour sied a false negative cytology is ob- is somewhat less sensitive for tumours of (28,29). tained (31). Reports have also indi- less than 20 mm diameter (28,29). cated that occasionally the tumour may Methods to establish It is unlikely that this examination spread along the needle tract (32). The histopathological diagnosis will ever become the primary method major disadvantage is that these biop- to detect small and fully resectable can- sies are carried out only once the tu- The many methods that have been cers, because it is never used before mour is large enough to be seen on ul- used to provide specimens for histologi- some other technique (ERCP, CT scan, trasound or CT scan, and in most cal diagnosis are shown in Table 7. etc) has already raised the suspicion of instances, by then it is too late for cura- Every method has certain specific limi- tive removal of the malignancy. Thus,

58 CAN JGASTROENTEROL VOL 9NO 1JANUARY/FEBRUARY 1995 in most instances these biopsies are only used to confirm by histology the presence of unresectable cancer. Direct cytology is now possible during endoscopic ultrasonography (33). The aspiration needle is inserted directly into the small tumour. Although data from a prospective study are not yet available, this method may surpass the accuracy of other types of biopsies. All these methods have a common defect: they exhibit low sensitivity but high specificity. In other words, if no cancer cells are found, malignancy is not excluded with certainty, but the presence of cancer cells provides an un- questionable diagnosis of malignancy. The major limitation is that many of these tumours are desmogenic and can- Figure 8) Algorithm to differentiate carcinoma from chronic pancreatitis. CT Computed tomogra- cer cells may be difficult to find. This phy; ERCP Endoscopic retrograde cholangiopancreatography; US Ultrasonography also holds, not only for aspiration cytology, but also for surgical biopsies symptoms suggestive of pancreatic dis- ultrasound, a guided fine-needle biopsy (34). ease without previous work-up. In is carried out. A positive biopsy for a tu- these patients, the first examination or- mour is diagnostic, but a negative one CLINICAL APPROACH TO dered is the abdominal ultrasound. If does not exclude malignancy. If the ul- DIAGNOSIS this is negative, a CT scan is carried out. trasound is negative, a dynamic CT There are three questions that need If this is also normal and if pancreatic scan may demonstrate the lesion and a to be answered during investigation: disease is strongly suspected, an ERCP CT guided biopsy may provide a diagno- first, whether chronic pancreatic dis- follows. If this is also negative, in the sis for malignancy. If, however, the bi- ease is present; second, whether this is presence of a strong clinical suspicion, opsy yields no malignant cells, an ERCP benign or malignant; and finally, a secretin test is carried out. is carried out to assess ductal anatomy. whether a malignant neoplasm is still Some clinicians still use pancreatic The role of endoscopic ultrasonogra- curatively resectable. Before the intro- function tests and even recent research phy combined with endoscopic ultra- duction of ultrasound and CT scan, pa- papers have used them (11,16,35). This sound guided cytology needs to be tients were referred to gastroenterolo- is why these tests were reviewed in the further evaluated. The main diagnostic gists because of abdominal pain, first section of the paper, even though role of this test will be to assess the na- diarrhea, weight loss or jaundice. The there may be little indication for their ture of tumours or cysts that are too gastroenterologist’s job was to diagnose utilization. Specifically, because of small for regular echography or CT scan these complex problems by means of their poor predictive value, presently guided fine-needle biopsy. laboratory investigation, indirect imag- available ‘screening tests’ are not cost- The third objective of investigation ing techniques and, since the 1970s, by effective. For all practical purposes is to establish whether a malignancy is ERCP. This has changed with the intro- there are only two pancreatic function resectable in patients in whom distant duction of both echography and CT tests that are still of use: the 72 h fecal metastases have been excluded. In the scanning. fat balance before and during pancre- past, angiography used to be employed Presently, patients are referred be- atic enzyme administration and the se- to assess vascular invasion. As endo- cause of suspected pancreatic disease cretin test. The first is used in the scopic ultrasound becomes more and detected as an incidental finding on ul- course of investigations of patients more established, this will become the trasound or CT scan, frequently ordered with steatorrhea. Because the secretin method of choice because it can assess for reasons unrelated to suspected pan- test is more sensitive than any of the most accurately size, vascular invasion creatic disease. These patients do not imaging methods (14), it is used where and lymph node involvement. need pancreatic investigation to prove chronic pancreatitis is suspected but In spite of the major advances in the presence of pancreatic disease and, the ERCP is still normal. methods of investigation, mortality due in contrast to past practice, will not un- The methods used to achieve the to cancer of the pancreas has not di- dergo function tests but will proceed di- second objective, ie, to differentiate minished during the past 20 years (36). rectly to ERCP. between chronic pancreatitis and car- This is because cancers of the pancreas There are, however, patients who cinoma, is reviewed in the algorithm can grow to considerable size before are still referred for investigation of shown in Figure 8. If a mass is found on they cause symptoms. Once symptoms BECK are present, it is still difficult to differ- deficiency. Gastroenterology multi-institutional survey. Radiology entiate chronic pancreatitis from can- 1984;86:1580-2. 1980;135:15-22. cer unless the cytology is positive. 8. Lankisch PG, Schreiber A, Otto J, 21. Cotton BP, William CB. Practical et al. Pancreolauryl test: Evaluation of a Gastrointestinal Endoscopy, 3rd edn. None of the tests can diagnose cancers tubeless pancreatic function test in Boston: Blackwell Scientific Publications, less than 2 cm in diameter, except in comparison with other indirect and direct 1990:85-156. the rare instance where a small tumour tests for exocrine pancreatic function. 22. Deltenre M, De Reuck M, De Koster E. obstructs the papilla. Those tests that Dig Dis Sci 1983;28:490-3. Endoscopic retrograde can diagnose small and resectable tu- 9. Cavallini G, Piubello W, Brocco G. cholangiopancreatography in the Reliability of the Bz-Ty-PABA and the diagnosis of 247 pancreatic malignancies. mours, ie, ERCP and endoscopic echo- pancreolauryl test in the assessment of A reappraisal. Acta Gastroenterolog Belg graphy, are done only once a suspicion exocrine pancreatic function. Digestion 1987;50:102-11. of pancreatic disease has arisen on the 1983;27:129-37. 23. Alpern MB, Sandler MA, Kellman GM. basis of less sensitive investigations. 10. Brugge WR, Goff JS, Allen NC. Chronic pancreatitis: Ultrasonic features. Even if tumours are discovered early, Development of a dual label Schilling Radiology 1985;155:215-9. test for pancreatic exocrine function 24. Karasawa E, Goldberg HI, Moss AA. CT surgery is difficult and has considerable based on the differential absorption of pancreatogram in carcinoma of the mortality, and radiotherapy and cobalamin bound to intrinsic factor and pancreas and chronic pancreatitis. chemotherapy remain ineffective. Un- R protein. Gastroenterology Radiology 1983;148:489-93. til a very sensitive and accurate screen- 1980;78:937-49. 25. Freeny PC, Marks WM, Ryan JA. ing blood test that can detect very 11. Marotta F, Labadarios D, Frazer L, Pancreatic ductal adenocarcinoma: Girdwood A, Marks IN. Fat soluble diagnosis and staging with dynamic CT. small cancers has been developed and vitamin concentration in chronic Radiology 1988;166:125-33. until improvement in therapy has been alcohol-induced pancreatitis. 26. Stark DD. The liver, pancreas and spleen. achieved, the high mortality due to Relationship with steatorrhea. In: Higgins CB, Hricak H, eds. Magnetic cancer of the pancreas will remain un- Dig Dis Sci 1994;39:993-8. Resonance Imaging of the Body. New altered. 12. Dreiling DA. Investigation of pancreatic York: Raven Press, 1987:347-72. function. In: Beck IT, Sinclair DG, eds. 27. Ishizaki Y, Wakayama T, Okada Y, Exocrine Pancreas. London: Churchill, et al. Magnetic resonance 1971:154-66. cholangiography for evaluation of ACKNOWLEDGEMENTS: I am indebted to 13. Nakanishi K, Kobayashi T, Miyashita H, obstructive jaundice. 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