8/19/2019 1-s2.0-S000296100700342X-main

http://slidepdf.com/reader/full/1-s20-s000296100700342x-main 1/4

Endoscopic ultrasound and early diagnosis of pancreatic cancer

Lars Helmstaedter, M.D., Juergen Ferdinand Riemann, M.D.* Department of Medicine C, Klinikum Ludwigshafen, Academic Hospital of the Johannes Gutenberg-University of Mainz, Medical Department C,

Klinikum Ludwigshafen gGmbH, Bremserstrasse 79, D-67063 Ludwigshafen, Germany

Abstract

Incidence of pancreatic cancer has increased, but prognosis remains poor. Curative treatment is

dependent on early diagnosis. Endoscopic ultrasound (EUS) has been described as highly sensitive and

accurate in staging, superior to other imaging modalities in early publications. With rapid advances in

technology, other imaging techniques have reached better results. EUS still has the highest accuracy in

assessing tumor size and lymph node involvement. For assessment of tumor respectability, a combination

of a computed tomography (CT) scan and EUS seems to be the procedure with the highest accuracy.Promising new techniques might improve the diagnostic yield of EUS. But there are several reasons for

failure, and EUS shows a high interobserver variety. Nevertheless, EUS proved to have a high negative

predictive value. Screening for pancreatic cancer and its precursor lesions in the general population is not

feasible, but high-risk subpopulations could be suitable targets for screening, preferably with an EUS- and

CT-based protocol. © 2007 Excerpta Medica Inc. All rights reserved.

Keywords:  Pancreatic cancer; Early detection; Endoscopic ultrasound

The incidence of pancreatic cancer has increased continu-ously over the last decades. Despite rapid improvements inimaging technologies and therapeutic modalities, the prog-

nosis remains poor. The overall 5-year relative survival ratefor 1996 to 2002 is estimated at 5.0%   [1].   If data arecritically reviewed,   it seems to be even less. Carpelan-Holmström et al   [2]   found a 5-year survival rate for pan-creatic ductal adenocarcinoma of 0.2%. At the time of diagnosis, only 7% of pancreatic cancers are found to belocalized to the organ without locoregional spreading ordistant metastases (American Joint Committee on Cancerstage I) and therefore resectable in a curative intention.Even if they are found to be in stage I, the prognosis remainspoor with a 5-year survival rate of 19.6%  [1].  These dataunderline the importance of early diagnosis of pancreaticcancer, but pain, jaundice, weight loss, and obstruction

usually are late symptoms.

Endoscopic UltrasoundOne of the most promising imaging techniques to detect

early pancreatic cancers is endoscopic ultrasound (EUS).This method is able to detect focal lesions as small as 2 to3 mm with the possibility to get tissue samples by fine-needle aspiration (FNA) or true-cut needle biopsy for his-

topathological examination. At present, there are 3 funda-mental different techniques of EUS available: (1)electronic or mechanical radial scanning scopes, in which

the electronic scanning scopes seem to produce betterB-mode image quality with no apparent difference inmaneuverability, endurance, and endoscopic images  [3];(2) linear scanning scopes; and (3) radial or linear scan-ning probes for use with standard scopes or alone. Fre-quencies range from 5 to 20 MHz for scopes up to 30MHz for probes. The accuracy in staging of pancreaticcancer is equivalent for radial and linear scanners [4], inwhich radial scanners offer a better overview of sur-rounding structures (Fig. 1),   whereas linear scanners al-low the safe execution of tissue sampling. In relation topancreatic cancer, indications for EUS are persistent epi-gastric and/or back pain, acute onset of diabetes in the

elderly, unclarified weight loss, and suspect results inultrasonography, especially in individuals over 45 yearsof age and in high-risk individuals (eg, persons with astrong family history of pancreatic cancers, with Peutz-Jeghers syndrome, or multiple endocrine neoplasia). EUSis a highly sensitive method, but results for accuracydiffer. Whereas initial studies showed excellent accuracy,results in later publications declined (Table 1 [5–11]). If tissue diagnosis is necessary before therapy, EUS-guidedFNA should be the method of choice. EUS-FNA is highlysensitive (84%), specific (97%), and accurate (84%) andhas a high positive predictive value (99%) with rare

* Corresponding author. Tel.:   49-0621-503-4100; fax:   49-0621-

503-4114.

 E-mail address:  ToddMc@baylorhealth.edu

The American Journal of Surgery 194 (Suppl to October 2007) S87–S90

0002-9610/00/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved.

doi:10.1016/j.amjsurg.2007.05.009

8/19/2019 1-s2.0-S000296100700342X-main

http://slidepdf.com/reader/full/1-s20-s000296100700342x-main 2/4

major complications but with a low negative predictivevalue of only 64% [12]. If pancreatic cancer is suspectedand if EUS-FNA is negative, cancer cannot be excludedand operation will be the next step despite positive ornegative FNA.

Comparing EUS As mentioned earlier, early studies showed high sensi-

tivity and accuracy for EUS. In most studies, EUS wassuperior or at least equal to other imaging modalities re-garding sensitivity, determining tumor size and   extent,lymph node involvement and vascular infiltration  [6,13].With rapid advances in technology, first of all, computedtomography (CT) and magnetic resonance imaging (MRI)have reached better results. Compared with helical CT, MRI(Fig. 2),  and angiography in a prospective study with his-topathological or surgical confirmation of results, helicalCT had the highest accuracy in assessing extend of primarytumor, locoregional extension, vascular invasion, distantmetastasis, tumor TNM stage and tumor resectability,whereas EUS reached the highest accuracy in assessingtumor size and lymph node involvement. To predict tumorresectability, the combination of CT and EUS proved to bethe method with the highest accuracy compared with each

single technique. With regard to cost minimization, thecombination of CT and EUS seems to increase the pricecompared with each single method. However, if the cost of unnecessary explorative laparotomies were taken into ac-count, the cost minimization analysis favored a sequentialstrategy in which EUS was used as a confirmatory technique

in those patients in whom helical CT suggested resectabilityof the tumor [11].

 Improving EUS One of the major problems in diagnosing pancreatic

cancer is the discrimination between focal pancreatitis andpancreatic cancer. A promising technique seems to be thecontrast-enhanced EUS using perfusion characteristics todifferentiate between focal inflammation and pancreaticcarcinoma. The sensitivity and specificity of conven-tional EUS were 73.2% and 83.3% for pancreatic carci-noma, increasing to 91.1% and 93.3% with the contrast-enhanced power mode  [14].

Another major problem for EUS is the assessment of vascular invasion. Sensitivity and specificity of EUS are63% and 64% for vascular adherence and 50% and 58% forvascular invasion  [15].  In a pilot study of 22 patients, theadditional 3-dimensional reconstructions appeared to im-prove the evaluation of vessel–tumor relationships, but theacquisition system needs to be improved [16]. These prom-ising new techniques to improve EUS may enrich the ar-mamentarium for staging pancreatic cancer correctly, butthey need to be evaluated in further studies.

 Reasons for failureEUS is not a foolproof method for detecting pancreatic

neoplasm. It has a high interobserver variety even amongexperienced endosonographers   [17,18].   In addition, accu-racy of EUS seems to be dependent on further clinical andimaging information  [10].   Chronic pancreatitis, diffuselyinfiltrating carcinoma, a prominent ventral/ dorsal split, anda recent episode of acute pancreatitis are also possibleassociated factors that may increase the likelihood of afalse-negative EUS examination [19].

 Negative predictive valueNormal EUS examination findings seem to have a high

negative predictive value (NPV). In 2 studies with 76 and135 patients and a mean follow-up period of 23.9 and 25

months, respectively, none of the patients with clinicallyindeterminate suspicion of pancreatic cancer and a normalEUS developed pancreatic cancer [20,21], which means anNPV of 100%. In contrast, Soriano et al [11] found an NPVfor locoregional extension, lymph node involvement, andvascular invasion of merely 44%, 65%, and 74% confirmedby intraoperative or histopathological findings.

Screening for pancreatic cancer Pancreatic cancer is  a disease with a poor overall 5-year

survival rate of 5%  [1].  There are reports of a 4-year sur-vival rate of 78% in resected stage 1 ductal adenocarcino-mas of the pancreas 2 cm in size, in which 42% were notassociated with symptoms   [22].   These data suggest thatscreening and early detection of pancreatic neoplasia might

Fig. 1. Endoscopic ultrasound of an adenocarcinoma in the pancreatic head

with a maximum diameter of 4.2 cm.

Table 1

Results for accuracy of EUS in literature

Accuracy (%)

Legmann et al  [6], AJR Am J Roentgenol 1998 93

Akahoshi et al  [7], Br J Radiol 1998 94

Cannon et al [8],  Gastrointest Endosc 1999 78

Ahmad et al [9], Gastrointest Endosc 2000 69

Meining et al  [10], Gut 2002 72

Soriano et al  [11], Am J Gastroenterol 2004 63

S88   L. Helmstaedter and J.F. Riemann / The American Journal of Surgery 194 (Suppl to October 2007) S87–S90

8/19/2019 1-s2.0-S000296100700342X-main

http://slidepdf.com/reader/full/1-s20-s000296100700342x-main 3/4

improve the dismal outcome of pancreatic cancer. There aremorphologically well-defined noninvasive precursor lesionsfor invasive pancreatic cancer, including pancreatic intra-ductal neoplasia and intraductal papillary mucinous neo-plasms (IPMNs). The treatment of these precursor lesionsmight prevent their progression to invasive cancer, as it is

well experienced in other organs. Because of the low inci-dence of pancreatic cancer and the lack of accurate, inex-pensive, and noninvasive diagnostic tests for early disease,screening for pancreatic cancer and its precursor lesions inthe entire population is not reasonable. But there are someknown high-risk subpopulations, such as members of fam-ilies with a strong history of pancreatic cancer or withhereditary pancreatitis and with distinct hereditary cancersyndromes, such as Peutz-Jeghers syndrome, hereditarybreast or ovarian cancer syndrome, familial atypical multi-ple mole melanoma syndrome, and hereditary nonpolyposiscolorectal cancer. Canto et al   [23]  screened for early pan-creatic neoplasia with an EUS-based and an EUS- and

CT-based [24] protocol. In the latter, pancreatic abnormal-ities were compared in high-risk individuals and controlsubjects. The EUS- and CT-based approach found 8 patientsamong 78 high-risk individuals with pancreatic neoplasmsconfirmed by surgery or FNA (6 patients with 8 benignIPMNs, 1 patient with an IPMN with progression to inva-sive ductal adenocarcinoma, and 1 patient with pancreaticintraepithelial neoplasia) and no pancreatic neoplasiaamong 149 control subjects. Abnormalities suggestive of chronic pancreatitis were more common in high-risk indi-viduals.

ConclusionsThe incidence of pancreatic cancer has increased over the

last decades. Despite rapid improvements in imaging tech-niques and therapeutic modalities, prognosis remains poor.One of the most promising techniques for early diagnosisseemed to be endoscopic ultrasound. EUS with or withoutfine-needle aspiration has a high sensitivity, whereas accu-racy in TNM staging differs. Optimistic results in earlystudies yielded to a more critical view. Compared with CTscan, MRI, and angiography, EUS showed the highest ac-curacy in assessing tumor size and lymph node involve-ment, whereas helical CT had the highest accuracy in as-sessing extend of primary tumor, locoregional extension,vascular invasion, distant metastasis, tumor TNM stage, andtumor resectability. The evaluation of tumor resectabilityshould be done by a minimum of 2 imaging techniques, inwhich the combination of CT scan and EUS proved to bethe method with highest accuracy at lowest cost or if neededintraoperatively. A detection of distand metastases withEUS is not possible. A normal EUS examination excludes apancreatic tumor with a high probability. The quality of EUS shows a high interobserver variance; additional rea-sons for failure are a chronic or recent episode of acutepancreatitis, diffusely infiltrating carcinoma, and a promi-nent ventral/ dorsal split. New techniques such as contrast-enhanced EUS or additional 3-dimensional reconstructionslook promising for improving EUS. Screening for pancre-atic cancer or its noninvasive precursor lesions in the gen-eral population is not feasible because of its low incidence,

but high-risk subpopulations, such as families with a stronghistory of pancreatic cancer, hereditary cancer syndromes,or pancreatitis, seem to be suitable targets for screeningprograms.

References[1] Ries LAG, Harkins D, Krapcho M, et al.   SEER Cancer Statistics

 Review, 1975–2003. National Cancer Institute, Bethesda, MD.[2] Carpelan-Holmström M, Nordling S, Pukkala E, et al. Does anyone

survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut 2005;54:385–7.

[3] Niwa K, Hirooka Y, Niwa Y, et al. Comparison of image qualitybetween electronic and mechanical radial scanning echoendoscopesin pancreatic diseases. J Gastroenterol Hepatol 2004;19:454–9.

[4] Gress F, Savides T, Cummings O, et al. Radial scanning and lineararray endosonography for staging pancreatic cancer: a prospectiverandomized comparison. Gastrointest Endosc 1997;45:243–50.

[5] Rösch T. Endoscopic ultrasonography: state of the art 1995, part 2.Gastrointest Endosc Clin N Am 1995;5:699–849.

[6] Legmann P, Vignaux O, Dousset B, et al. Pancreatic tumors: com-parison of dual-phase helical CT and endoscopic sonography. AJRAm J Roentgenol 1998;170:1315–22.

Fig. 2. (A) Endoscopic ultrasound of a carcinoma in the pancreatic head

and (B) corresponding MRI.

S89 L. Helmstaedter and J.F. Riemann / The American Journal of Surgery 194 (Suppl to October 2007) S87–S90

8/19/2019 1-s2.0-S000296100700342X-main

http://slidepdf.com/reader/full/1-s20-s000296100700342x-main 4/4