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2 Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. Introduction. Pancreatic ductal adenocarcinoma is the fourth leading cause ...
J Hepatobiliary Pancreat Surg (2004) 11:4–10 DOI 10.1007/s00534-002-0775-x

Pancreatic tumors: role of imaging in the diagnosis, staging, and treatment Dominique Delbeke1 and C. Wright Pinson2 1

Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 21st Avenue South and Garland, Nashville, TN 37232-2675, USA 2 Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Abstract Because most patients with pancreatic cancer present with biliary obstruction, percutaneous transhepatic cholangiopancreatography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP) is often performed first to relieve obstruction. Fine needle biopsy (FNA) provides a tissue diagnosis, but is often nondiagnostic due to sampling error. Computed tomography (CT) is the workhorse of oncology, but is poor at defining the nature of pancreatic lesions. Small primary tumors are often not visualized. Fast magnetic resonance imaging (MRI) techniques allowing dynamic imaging after IV gadolinium and new contrast agents allow better characterization of the lesions for patients having contraindications for IV CT contrast agents. Magnetic resonance cholangiopancreatography (MRCP) allows noninvasive visualization of the biliary tree. Endoscopic ultrasonography (EUS) allows evaluation of the detailed regional anatomy with the possibility of FNA. 18F-Fluorodexoglucose (FDG) is the most common tracer used in positron emission tomography (PET), and most malignant tumors, including pancreatic carcinoma, have increased FDG uptake compared with normal cells. This functional imaging does not replace but is complementary to morphological imaging. FDG PET is particularly helpful: (1) for the diagnosis in patients with suspected pancreatic cancer in whom CT fails to identify a mass, or those in whom FNAs are nondiagnostic; (2) for staging by detecting CT-occult metastases; (3) for detecting recurrence; and (4) for monitoring therapy. Limitations include false-positive inflammatory processes and falsenegative carcinoma in patients with diabetes and hyperglycemia, and islet cell tumors. Key words Pancreas · Neoplasms · Emission computed tomography · Fluorodeoxyglucose

Offprint requests to: D. Delbeke Received: April 25, 2002 / Accepted: June 24, 2002

Introduction Pancreatic ductal adenocarcinoma is the fourth leading cause of death in the United States and is increasing in incidence. The preoperative diagnosis, staging, and treatment of pancreatic cancer remain challenging. The suspicion for pancreatic cancer is often raised by sonographic or computed tomography (CT) findings, including the presence of a low-attenuation pancreatic mass and dilatation of the pancreatic duct and/or biliary tree. CT is the most common diagnostic imaging modality utilized in the preoperative diagnosis of pancreatic cancer. In a multicenter trial,1 the diagnostic accuracy of CT for staging and resectability was 73%, with a positive predictive value for nonresectability of 90%, but more recent studies have reported accuracies of 85% to 95%, likely related to improvements in CT technology.2,3 Unfortunately, interpretation of the CT scan is sometimes difficult in the setting of mass-forming pancreatitis or questionable findings such as enlargement of the pancreatic head without definite signs of malignancy or discrete mass.4,5 The diagnosis of locoregional lymph node metastases is also difficult with CT, because they often are small. In addition, small hepatic metastases (⬍1 cm) cannot reliably be differentiated from cysts.6 Therefore, the reported negative predictive value for nonresectability is less than 30%. Despite recent technical improvements in magnetic resonance imaging (MRI), including MR cholangiopancreatography (MRCP), the diagnostic performance of MRI remains similar to that of CT.7–10 Endoscopic ultrasound offers the possibility of tissue diagnosis with fine needle biopsy (FNA), but the field of view is limited.11–13 The accuracy of endoscopic retrograde cholangiopancreatography (ERCP) is 80% to 90% to differentiate a benign from a malignant pancreatic mass, including differentiation of tumor from chronic pancreatitis because of the high degree of resolution of ductal structures. The limita-

D. Delbeke and C.W. Pinson: FDG PET and pancreatic cancer

tions include false-negative findings when the tumor does not originate from the main duct, a 10% rate of technical failure, and up to 8% morbidity due to iatrogenic pancreatitis. The main advantages are the possibilities of interventional procedures and FNA, although this technique suffers from significant sampling error,14,15 with a false-negative incidence of 8%–17%. The difficulty in making a preoperative diagnosis is associated with two types of adverse outcomes. First, less aggressive surgeons may abort attempted resection due to a lack of tissue diagnosis. This is borne out by the significant rate of “reoperative” pancreaticoduodenectomy performed at major referral centers.16–18 A second type of adverse outcome, generated by failure to obtain a preoperative diagnosis, occurs when more aggressive surgeons inadvertently resect benign disease. This is particularly notable in those patients who present with suspected malignancy without an associated mass on CT scan. This has been reported to occur in up to 55% of patients in some series.19

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F-Fluorodexoglucose (FDG) positron emission tomography (PET) imaging in the preoperative diagnosis of pancreatic carcinoma In order to avoid these adverse outcomes, metabolic imaging with FDG PET has been used to improve the accuracy of the preoperative diagnosis of pancreatic carcinoma. Most malignancies, including pancreatic carcinoma, demonstrate increased glucose utilization due to an increased number of glucose transporter proteins and increased hexokinase and phosphofructokinase activity.20,21 There is recent evidence that the overexpression of glucose transporters by malignant pancreatic cells contributes to the increased uptake of FDG by these neoplasms.22,23 In 12 studies,24–35 the performance of FDG PET to differentiate benign from malignant lesions ranged from 85% to 100% for sensitivity, 67% to 99% for specificity, and 85% to 93% for accuracy. In the majority of these studies the accuracy of FDG PET imaging was superior to that of CT. For example, in the study of Delbeke et al.,35 the sensitivity and specificity of FDG PET imaging was 92% and 85%, respectively, compared with 65% and 62% for CT. In addition, the sensitivity of CT imaging improves with the size of the lesion, but the sensitivity of FDG PET is not as dependent on lesion size.36 In a study of 35 patients comparing EUS, PET, and CT, the sensitivity for detection of pancreatic cancer was higher for EUS (93%) and FDG PET (87%) than for CT (53%).13 A comprehensive tabulated review of the PET literature (387 patient’s studies) has reported weighted averages for FDG PET sensitivity and specificity of 94% and 90%, respectively, compared with 82% and 75% for CT.37

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Together, these series support the conclusion that FDG PET imaging may represent a useful adjunctive study in the evaluation of patients with suspected pancreatic cancer (Fig. 1). Preliminary reports suggest that the degree of FDG uptake has a prognostic value. The degree of uptake can be measured with the standard uptake value (SUV); that is, the radioactivity in a region of interest normalized for the dose administered and the body weight. Nakata et al.38 noted a correlation between SUV and survival in 14 patients with pancreatic adenocarcinoma. Patients with an SUV of more than 3.0 had a mean survival of 5 months, compared with 14 months in those with an SUV of less than 3.0. In a multivariate analysis of 52 patients with pancreatic carcinoma, the median survival of patients with an SUV of more than 6.1 was 5 months, compared with 9 months for patients with an SUV of less than 6.1.39 Limitations of FDG PET imaging The high incidence of glucose intolerance and diabetes exhibited by patients with pancreatic pathology represents a potential limitation of this modality in the diagnosis of pancreatic cancer. Elevated serum glucose levels result in decreased FDG uptake in tumors by up to 50% due to competitive inhibition. Several studies have reported a lower sensitivity in hyperglycemic compared with euglycemic patients.27,32,35 For example, in a study of 106 patients with a disease prevalence of 70%,32 FDG PET had a sensitivity of 98% in a subgroup of euglycemic patients versus 63% in hyperglycemic patients. This has led some investigators to suggest that the SUV be corrected according to serum glucose level.40–43 In the studies of Delbeke et al.35 and Diederichs et al.,43 the presence of elevated serum glucose levels and/or diabetes mellitus may have contributed to false-negative interpretations, but correction of the SUV for serum glucose level has not significantly improved the sensitivity of FDG PET in the diagnosis of pancreatic carcinoma. The true impact of serum glucose levels on the accuracy of FDG PET in pancreatic cancer and other neoplasms remains controversial. False-negative studies may also occur when the tumor diameter is less than 1 cm (i.e., small ampullary carcinoma). Ampullary carcinomas arise from the ampulla of Vater and have a better prognosis than pancreatic carcinoma because they cause biliary obstruction and are diagnosed earlier in the course of the disease. The detection rate with FDG imaging is only 70%– 80%, probably because of their smaller size at the time of clinical presentation. Both glucose and FDG are substrates for cellular mediators of inflammation. Some benign inflammatory lesions, including chronic and acute pancreatitis with

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or without abscess formation, can accumulate FDG and result in false-positive interpretations on PET images.27,30,44,45 In addition, post-stenotic pancreatitis can obscure FDG uptake in the tumor itself. False-positive studies are more frequent in patients with elevated Creactive protein and/or acute pancreatitis, with a specificity as low as 50%.45,46 Therefore, screening for acute inflammatory disease with serum C-reactive protein has been recommended.

D. Delbeke and C.W. Pinson: FDG PET and pancreatic cancer

Stage II disease is characterized by extrapancreatic extension (T stage), stage III by lymph node involvement

(N stage), and stage IV by distant metastases (M stage). T staging can only be evaluated with anatomical imaging modalities that demonstrate the relationship between the tumor, adjacent organs, and vascular structures. Endoscopic ultrasonography (EUS) appears to be more sensitive than CT for the evaluation of vascular invasion of the portal and superior mesenteric veins.13 Functional imaging modalities cannot replace anatomical imaging in the assessment of local tumor resectability. Both FDG PET and CT are poor for N staging, probably due to the proximity of regional lymph nodes to the primary tumor.25,31,35 However, FDG PET is more accurate than CT for M staging. In the study of Delbeke

Fig. 1a,b. A 59-year-old man presented with pain and jaundice. Endoscopic retrograde cholangiopancreatography (ERCP) was performed and a stent placed to relieve biliary obstruction. A computed tomography (CT) scan of the abdomen (a) demonstrated a 3 ⫻ 4-cm mass in the head of the pancreas with suspected vascular invasion. Fine needle aspiration on three separate occasions was nondiagnostic. 18F-

Fluorodexoglucose (FDG) positron emission tomography (PET) imaging (b) was performed and demonstrated a focus of uptake in the region of the pancreatic mass extending to the region adjacent to the superior mesenteric artery. Endoscopic ultrasound confirmed vascular invasion, and biopsy of the FDG-avid portion of the mass confirmed pancreatic carcinoma

FDG PET for staging pancreatic carcinoma

a

b

D. Delbeke and C.W. Pinson: FDG PET and pancreatic cancer

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a

b Fig. 2a,b. A 69-year-old man with a history of Whipple procedure for pancreatic carcinoma 2 years earlier presented with increasing fatigue and malaise. A computed tomography (CT) scan of the abdomen (a) demonstrated soft-tissue densities in the portocaval region adjacent to the superior mesenteric

artery and anterior to the inferior vena cava. These metastatic nodal masses were markedly hypermetabolic on FDG PET imaging (b). Physiologic FDG uptake is also seen in the renal collecting system and in the bowel anteriorly

et al.,35 metastases were diagnosed both on CT and PET in 10 of 21 patients with stage IV disease, but PET demonstrated hepatic metastases not identified or equivocal on CT, and/or distant metastases unsuspected clinically in 7 additional patients (33%). In 4 patients (19%), neither CT nor PET imaging showed evidence of metastases, but surgical exploration revealed miliary carcinomatosis in 3 patients and a small liver metastasis in 1 patient. FDG PET is sensitive for the detection of hepatic metastases, but false-positive findings have been reported in the liver of patients with dilated bile ducts and inflammatory granulomas.47 The tabulated review of the PET literature has reported weighted averages for FDG PET sensitivity and specificity of 83%

and 82%, respectively, compared with 65% and 61% for CT for staging pancreatic carcinoma (461 patient’s studies).37

Impact of FDG PET on the management of patients with pancreatic carcinoma The rate at which FDG PET may lead to alterations in clinical management clearly depends on the specific therapeutic philosophy employed by the evaluating surgeon. In the study of Delbeke et al.,35 the surgeons advocate pancreaticoduodenectomy only for those patients with potentially curable pancreatic cancer, and

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they take an aggressive approach to resection, including en-bloc retroperitoneal lymphadenectomy and selective resection of the superior mesenteric-portal vein confluence when necessary, while the majority of patients with nonmalignant biliary strictures are managed without resection. In that series of 65 patients, the application of FDG PET imaging in addition to CT altered the surgical management in 41% of the patients, in 27% by the detection of CT-occult pancreatic carcinoma and in 14% by the identification of unsuspected distant metastases, or by the clarification of the benign nature of lesions that were equivocal on CT.35

FDG PET for monitoring therapy and for the detection of recurrent pancreatic carcinoma Preliminary studies suggest that neoadjuvant chemoradiation improves the resectability rate and survival of patients with pancreatic carcinoma.48,49 A pilot study determined that FDG PET imaging may be useful for the assessment of tumor response to neoadjuvant therapy and for the evaluation of suspected recurrent disease following resection.36 Nine patients underwent FDG PET imaging before and after neoadjuvant chemoradiation therapy. FDG PET successfully predicted histological evidence of chemoradiation-induced tumor necrosis in all four patients who demonstrated at least a 50% reduction in tumor SUV following chemoradiation. Among these patients, none showed a measurable reduction in tumor diameter as assessed by CT. The four patients who had FDG PET evidence of tumor response went on to successful resection, all showing 20% to 80% tumor necrosis in the resected specimen. Three patients showed stable FDG uptake and two showed increasing FDG uptake, indicative of tumor progression. Of the two patients with progressive disease demonstrated by FDG PET, one showed tumor progression on CT, and the other demonstrated stable disease. Of the five patients who showed no response by FDG PET, the disease could be subsequently resected in only two, and only one patient who underwent resection showed evidence of chemoradiation-induced necrosis in the resected specimen. Another pilot study suggests that the absence of FDG uptake at 1 month following chemotherapy is an indicator of improved survival.50 Definitive conclusions regarding the role of FDG PET in assessing treatment response will obviously require evaluation in a larger population of patients. However, given the poor track record of CT in assessing histological response to neoadjuvant chemoradiation, the potential utility of FDG PET in this capacity deserves further investigation. The majority of reports concerning the clinical utilization of FDG PET imaging for pancreatic malignancy

D. Delbeke and C.W. Pinson: FDG PET and pancreatic cancer

have emphasized the identification of recurrent nodal or distant metastatic disease (Fig. 2). In a preliminary study,36 8 patients were evaluated for possible recurrence because of either indeterminate CT findings or a rise in serum tumor marker levels. All were noted to have significant new regions of FDG uptake, 4 in the surgical bed and 4 in new hepatic metastases. In all patients, metastasis or local recurrence was confirmed pathologically or clinically. Another study, of 19 patients, concluded that FDG PET added important incremental information in 50% of the patients, resulting in a change of therapeutic procedure.51 This series included patients with elevated serum tumor marker levels but no findings on anatomical imaging. Therefore, FDG PET may be particularly useful: (1) when CT identifies an indistinct region of change in the bed of the resected pancreas that is difficult to differentiate from postoperative or postradiation fibrosis, (2) for the evaluation of new hepatic lesions that may be too small to biopsy, and (3) in patients with rising serum tumor marker levels and a negative conventional workup.

Summary FDG PET imaging is a sensitive and specific adjunct to CT when applied to the preoperative diagnosis of pancreatic carcinoma, particularly in patients with suspected pancreatic cancer in whom CT fails to identify a discrete tumor mass or in whom FNAs are nondiagnostic. By the provision of preoperative documentation of pancreatic malignancy in these patients, laparotomy may be undertaken with a curative intent, and the risk of aborting resection due to diagnostic uncertainty is minimized. FDG PET imaging is also useful for M staging and restaging by detecting CToccult metastatic disease, and allowing nontherapeutic resection to be avoided altogether in this group of patients. As is true with other neoplasms, FDG PET can differentiate post-therapy changes from recurrence and holds promise for monitoring neoadjuvant chemoradiation therapy.

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