Islet-cell tumors of the pancreas: Spectrum of MDCT findings. A pictorial essay.

David S. Lee, MD, R. Brooke Jeffrey, MD, and Aya Kamaya, MD

lthough pancreatic islet-cell tumors account for only 1% to 5% of all pancreatic neoplasms, they represent an important subset of pancreatic neoplasms due to their substantially improved prognosis compared to pancreatic adenocarcinoma.1,2 Pancreatic islet-cell tumors, also referred to as neuroendocrine tumors, may present with a broad spectrum of clinical and imaging manifestations, sometimes quite dramatic, depending on whether lesions are solitary or multiple, syndromic or nonsyndromic, inherited or sporadic, or benign or malignant. The role of the radiologist in imaging pancreatic islet-cell tumors is to localize the tumor and evaluate the extent of disease, which in turn helps determine whether the patient is an operative candidate and helps guide therapy. Ninety-five percent of pancreatic isletcell tumors are solitary and sporadic. Generally, these do not exhibit hormonal hypersecretion (nonsyndromic) and are clinically silent until they grow large enough to cause symptoms.
Dr. Lee is a Body Imaging Fellow, Dr. Kamaya is an Assistant Professor, and Dr. Jeffrey is a Professor and Abdominal Imaging Section Chief, Department of Radiology, Stanford University Medical Center, Stanford, CA.

On the other hand, hyperfunctioning islet-cell tumors (referred to as syndromic islet-cell tumors) manifest much earlier, and at a much smaller size due to symptoms caused by hormonal oversecretion. Often these syndromic tumors are barely visible by imaging, in spite of a dramatic clinical presentation. These tumors are classified according to the predominant hormone of oversecretion: insulinoma, gastrinoma, vasoactive intestinal peptide-secreting tumors (VIPoma), glucagonoma, somatostatinoma, and growth-hormone-releasing factor-secreting tumors (GRFomas). Insulinomas account for 50% of all islet-cell tumors and are the most common islet-cell tumor subtype.6 The majority of insulinomas (80% to 90%)

are benign, solitary and are <2 cm at presentation.7 These tumors cause fluctuations in serum glucose levels in patients, with associated morbidity related to severe hypoglycemia, occasionally leading to multiple seizures. Surgical resection of insulinomas is the treatment of choice, with symptoms promptly resolving after resection. Pancreatic islet-cell tumors other than insulinomas have a higher malignancy rate, approaching 60% to 90%.1 Gastrinomas are the second most common islet-cell tumor, with approximately 25% associated with multiple endocrine neoplasia (MEN-1).4 Resection of gastrinomas is often difficult due to locally invasive features or metastatic disease in more than half of

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FIGURE 1. Gastrinoma triangle. The gastrinoma triangle is an anatomic triangle bounded by the junction of the cystic duct insertion on the common bile duct, the body of the pancreas, and the junction of the second and third portions of the duodenum. Contents of the gastrinoma triangle are highlighted in this diagram, whereas regions outside of the triangle are darkened. Illustration courtesy of Amy N. Morris.

FIGURE 2. Hepatic metastases. Octreotide scan demonstrates several somatostatinpositive foci in the right-upper abdomen in a patient with history of pancreatic islet-cell tumor, which is consistent with hepatic metastases in distribution and appearance.

FIGURE 3. Ultrasound appearance of pancreatic islet-cell tumor. Intraoperative ultrasound image shows well-circumscribed hypoechoic pancreatic islet-cell tumor with hypervascular, predominantly peripheral, vascularity.

FIGURE 4. Typical hypervascular pancreatic islet-cell tumor on computed tomography (CT). (A) Typical appearance of well-circumscribed, small, hypervascular, pancreatic-tail, islet-cell tumor (insulinoma) on arterial-phase imaging (arrow). (B) Tumor retains contrast on delayed imaging (arrow).

patients.1 When a gastrinoma is suspected, one should carefully inspect the gastrinoma triangle, an anatomic triangle bounded by the junction of the cystic duct insertion on the common bile duct, the body of the pancreas, and the junction of the second and third portions of the duodenum (Figure 1). About 85% to 90% of gastrinomas are present within the gastrinoma triangle; the search for this tumor should not be limited solely to the pancreas but should include the boundaries of this anatomic triangle. Similarly, VIPomas, somatostatinomas, and GRFomas may also arise outside of the pancreas.4 Unlike sporadic islet-cell tumors, inherited pancreatic islet-cell tumors are usually multiple in location and most often related to C

FIGURE 5. (A) The same insulinoma as seen in Figure 4 is shown on magnetic resonance imaging (MRI) with low T1 signal intensity on the precontrast image (arrow) and it enhances on T1-weighted (T1W) postcontrast images, approaching signal intensity of surrounding normal pancreatic parenchyma on arterial-phase images (B, arrow). This tumor is difficult to identify on T2-weighted (T2W) fat-suppressed images (C), however, with only subtle signal abnormality noted (arrow).

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A B A

FIGURE 6. Intraoperative ultrasound of insulinoma for the same patient shown in Figures 4A and 4B. (A) Well-circumscribed oval hypoechoic pancreatic mass is visible. (B) Both peripheral and central vascular blood flow is demonstrated.

FIGURE 7. Maximum intensity projection (MIP) appearance of pancreatic islet-cell tumor. Hypervascular pancreatic islet-cell tumor seen adjacent to SMV near portal confluence (arrow) on arterial-phase MIP.

FIGURE 8. Utility of multiplanar reformations. (A) curved planar reformation (CPR) and MIP are often useful for delineating the anatomic relationship of tumor with adjacent pancreatic tissue and vessels. (B and C) Reformatted images show hypervascular pancreatic islet-cell tumor causing mass effect on the mid portion of pancreatic duct (arrow).

A MEN-1. They can also be seen with other syndromes such as Von Hippel-Lindau, tuberous sclerosis and neurofibromatosis type 1.3 Whether pancreatic lesions associated with MEN-1 are more likely benign or malignant is still much debated. Differentiation between inherited and sporadic etiologies is important not only because of their different imaging presentation, but also because they undergo differenttherapies.4,5 Imaging is helpful in determining

FIGURE 9. Differences in appearance based on phase of imaging. (A) Arterial-phase image demonstrates multiple hypervascular liver metastases from pancreatic islet-cell tumor. (B) Metastases are less conspicuous on venous-phase images.

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A B extent of disease, with implications on the p a t i e n t s o v e r a l l p r o g n o s i s . Tu m o r growth and spread is considered the major determinant of patient survival. Pancreatic islet-cell tumors spread first to regional lymph nodes, then to the liver, bone, and rarely, to distant sites such as the lung or brain. Lymphovascular invasion is an important feature correlating to survival.8 Fifty percent to seventy percent of deaths in patients with metastatic disease are thought to be caused by tumor

FIGURE 10. Differences in appearance based on phase of imaging. (A) Axial CT in arterial phase shows a large heterogeneous pancreatic islet-cell tumor. (B) Venous-phase image demonstrates late retention of contrast by tumor.

FIGURE 11. Inherited syndromic patient with pancreatic islet-cell tumors. Coronal multiplanar reformation (MPR) image shows two well-circumscribed hypervascular pancreatic islet-cell tumors in a patient with several gastrinomas (arrows).

FIGURE 12. Inherited syndromic patient with cysts and pancreatic islet-cell tumors. (A and B) Axial CT images in arterial phase show multiple pancreatic cysts and hypervascular islet-cell tumor (arrow) in a patient with Von Hippel-Lindau syndrome.

FIGURE 13. Inherited syndromic patient with cysts and pancreatic islet-cell tumors. (A and B) CPR images demonstrate multiple pancreatic cysts as well as several heterogeneously enhancing pancreatic islet-cell tumors (arrows) in a patient with Von Hippel-Lindau syndrome.

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FIGURE 14. Typical hypervascular liver metastases. Axial CT image in arterial phase shows multiple small hypervascular liver metastases from pancreatic islet-cell tumor (arrows).

FIGURE 15. Necrotic liver metastases and changes of chronic pancreatitis. Axial image shows two large, heterogeneously enhancing, centrally necrotic liver masses with several small hypervascular liver lesions, compatible with metastatic disease in a patient with known pancreatic islet-cell tumor. There are several punctate pancreatic-tail calcifications as well as pancreatic duct dilation and parenchymal atrophy, suggesting changes of chronic pancreatitis.

FIGURE 16. Regional lymphadenopathy. (A and B) Axial CT images show regional adenopathy around the abdominal aorta near the origin of the celiac artery in a patient with pancreatic islet-cell tumor (arrows).

progression.4

Imagingoptions
Computed tomography (CT) is the initial imaging modality of choice, but is estimated to detect only 60% to 70% of primary pancreatic insulinomas and gastrinomas. 9,10 Magnetic resonance

imaging (MRI), intraoperative ultrasound, endoscopic ultrasound, selective angiography and portal venous sampling may serve as adjunctive methods of evaluating disease. 11 Recent literature suggests that MRI may be at least as sensitive as multiphasic CT in detecting pancreatic islet-cell tumors. 12 In our

experience, a multimodality approach is useful for diagnosing and staging pancreatic islet-cell tumors as well as helping toguidesurgery(Figures2-6).

Treatment
Preoperative imaging evaluation is important for surgical planning because

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FIGURE 17. Bone metastases. Axial CT image viewed in bone algorithm shows sclerotic bone lesions in lumbar vertebra of a patient with pancreatic islet-cell tumor, presumed to represent metastatic disease.

FIGURE 18. Isoattenuating pancreatic islet-cell tumor. CPR image shows isoattenuating pancreatic-head mass (arrow) exerting mass effect upon the pancreatic duct.

FIGURE 19. Necrotic islet-cell tumor with liver metastases. Axial CT shows large necrotic pancreatic islet-cell tumor (white arrow). Several small hypervascular liver metastases are present (black arrows). (B) Coronal reformation image demonstrates large peripherally enhancing, centrally necrotic pancreatic mass and several hypervascular liver metastases (arrows).

FIGURE 20. Hypoattenuating appearance of pancreatic islet-cell tumor. Axial CT shows small peripherally hypervascular pancreatic uncinate islet-cell tumor containing two small central hypoattenuating regions (arrow). (B) Coronal MIP better demonstrates peripheral enhancement and central low attenuation of mass (arrow).

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FIGURE 21. Unusual cystic appearance of pancreatic islet-cell tumor. (A) Axial CT in arterial phase demonstrates round, low-attenuation, wellcircumscribed lesion within pancreatic tail; this is an extremely atypical appearance for pancreatic islet-cell tumor. (B) Cystic-appearing lesion is redemonstrated on coronal MPR image. Lesion was confirmed pathologically as pancreatic islet-cell tumor.

FIGURE 22. Partially calcified pancreatic islet-cell tumor. Axial image demonstrates large heterogeneous pancreatic islet-cell tumor containing calcifications. There is heterogeneous attenuation of the liver with large, round hypodensity in the posterior right hepatic lobe, compatible with diffuse liver metastases. A large right renal cyst is incidentally seen.

resection is the only definitive curative treatment, regardless of benign or m a l i g n a n t p a t h o l o g y. O n e s h o u l d determine the location of the tumor within the pancreas, and assess presence of

multiple tumors, including tumors outside of the pancreas, and looking for evidence of local invasion or metastatic disease. 13 These findings will affect surgical candidacy and help guide the type

FIGURE 23. Partially calcified pancreatic islet-cell tumor. (A) On axial CT imaging, the tumor contains chunky central calcifications. (B) Mass interrupts pancreatic duct on coronal MPR image. MPR image also demonstrates course of distal common bile duct and remainder of pancreatic duct.

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A

FIGURE 24. Splenic artery encasement and narrowing. (A) CPR shows splenic artery encasement by hypodense pancreatic islet cell tumor. (B) Splenic artery encasement and mild narrowing also demonstrated on thin-slab MIP.

FIGURE 25. Splenic vein thrombus. Axial CT image in venous phase demonstrates focal filling defect within splenic vein (arrow) presumed to be due to patients pancreatic islet-cell tumor.

FIGURE 26. SMV encasement by tumor. SMV narrowing (teardrop sign) with flattening and acute angulation of the right lateral wall of the superior mesenteric vein (arrow) indicates presence of isoattenuating pancreatic islet-cell tumor. Appearance more commonly seen with pancreatic adenocarcinoma.

ofsurgerytobeperformed,suchasenucleation, partial, or rarely, total pancreatectomy.14 There are several therapeutic options for treating advanced disease from isletcell tumor. Liver metastases in patients with insulinomas and gastrinomas are estimated to be present in up to 35% to 74% of cases. 4 Chemotherapy has been used for metastatic disease with some success in limited trials.15 Interferon and octreotide, as well as hepatic artery embolization or ligation, have also been used.16,17Inselectcaseslivertransplantation has been performed. 14 There is some controversy over the efficacy of debulking for treatment of metastatic disease.15

CTtechnique
At our institution, most patients are initially evaluated with a pancreaticprotocol CT. We use 8- and 16-detector CT scanners in our hospital (Lightspeed, GE Healthcare, Chalfont St. Giles, U.K.) and a 64-detector scanner at our outpatient f a c i l i t y ( S O M ATO M S e n s a t i o n 6 4 , Siemens Healthcare, Malvern, PA). Fifteen to thirty minutes prior to the study, patients drink 1350 cc of VoLumen, a

FIGURE 27. Venous occlusion without arterial encasement. Coronal MPR image demonstrates occlusion of splenic vein with venous collateral formation around proximal splenic artery, but no encasement, in a patient with pancreatic islet-cell tumor.

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FIGURE 28. Portal vein with tumor thrombus. (A) Axial CT image in venous phase, shows portal vein expanded and filled with enhancing material, as well as numerous periportal and gastrohepatic venous collaterals, consistent with tumor thrombus within the portal vein from pancreatic islet-cell tumor. (B) Coronal MPR image confirms portal vein invasion (black arrow) with cavernous transformation (white arrow).

FIGURE 29. Portal vein with tumor invasion. (A) CPR image shows islet-cell tumor directly invading the portal vein (arrow). (B) Coronal reformation image demonstrates venous invasion (black arrow) of the portal vein extending directly from a large heterogeneous pancreatic body isletcell tumor (white arrow).

neutral oral contrast agent, (Bracco Diagnostics, Princeton, N.J.) and another 450 cc immediately prior to scanning. Oral contrast facilitates luminal distention of the stomach and duodenum. A scout image of the abdomen is initially acquired, followed by limited noncontrast images of the abdomen to

localize the pancreas (5 mm thickness). Approximately 140 cc of nonionic contrast (ISOVUE-370, Bracco Diagnostics) is subsequently administered intravenously at an injection rate of 4 cc/sec, with arterial-phase images acquired 40 seconds after injection (1.25 mm thickness, helical acquisition, 0.6

mm interval, 1.35:1 pitch) from the level of the diaphragm to the top of the iliac crests. Portal venous-phase images are obtained at a 60-second delay following injection (2.5 mm thickness, 1.25 mm interval, 1.35:1 pitch). Delayed images areroutinelyacquiredthroughthekidneys 3 minutes after contrast adminis-

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FIGURE 30. Interrupted duct from pancreatic islet-cell tumor. CPR shows abrupt termination of dilated pancreatic duct with isoattenuating pancreatic-head mass (arrow). A biliary stent had been placed.

tration(5mmthickness). The helically acquired volumetric data is postprocessed by specially trained technologists in our dedicated 3-dimensional laboratory to generate multiplanar reconstruction images including maximum intensity projections (MIPs), minimum intensity projections (MINIPs) and curved planar reformations (CPRs). These reconstructions provide better anatomic definition of key structures commonly affected by locally invasive pancreatic neoplasms (Figure 7), including thin-slab MIPs of the celiac origin, portal and splenic veins; CPRs of the superior mesenteric vein and artery, hepatic artery, gastroduodenal artery, splenic artery, distal common bile duct and pancreatic ducts; thin-slab MINIPs of the pancreatic ducts; and, coronal MPRs in the plane of the main portal vein through the entiretyofthepancreas.

Typicalimagingfindings
The typical appearance of a pancreatic islet-cell tumor is a wellcircumscribed, solitary, hypervascular mass (Figure 4). Because islet-cell tumors are generally soft, and lack associated desmoplastic reaction, they do not usually cause pancreatic duct obstruction or dilation. Mild distortion

of the duct may be seen due to adjacent mass effect or if the tumor is located near the mainpancreaticduct(Figure8). Typically, pancreatic islet-cell tumors and metastases are best seen during the late arterial phase (Figures 4, 9). On portal-venous phase, tumors will characteristically demonstrate late retention of contrast (Figures 4, 10). While arterial enhancement patterns are accepted as the most common imaging appearance, atypical enhancement patterns do occur, and varying opinions on optimal phase of enhancement have been reported.9,12,18,19,20 Given the variability in peak enhancement and enhancement patterns, multiphasic imaging is generally accepted as the best method to ensure optimal detection of pancreaticislet-celltumors. On ultrasound, pancreatic islet-cell tumors are generally hypoechoic and well circumscribed. Color Doppler imaging will reveal prominent vascularity of the tumor. Often the tumor is difficult to palpate surgically due to its soft texture. Intraoperative ultrasound is helpful in localizing small tumors and delineating their relationship to the main pancreatic duct and adjacent vessels (Figure6). In patients with inherited islet-cell

FIGURE 31. Isoattenuating islet-cell tumor causing double duct sign. (A) On CPR, a large, infiltrative, isoattenuating, pancreatic islet-cell tumor causes abrupt interruption and dilation of the pancreatic duct. (B) Mass and pancreatic duct dilation is confirmed on coronal minimum intensity projection imaging. (C) There is biliary duct dilation, which in conjunction with pancreatic duct dilation, causes a double duct sign; these imaging features are more typically associated with pancreatic adenocarcinoma.

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FIGURE 32. Regional lymphadenopathy suggesting local recurrence. (A) Patient underwent Whipple surgery for pancreatic islet-cell tumor. (A) Hypervascular aortocaval (arrow) and (B) portocaval lymph nodes (arrow) are seen on follow-up imaging, suggesting local recurrence.

B A commonly cited reason for difficulty in visualizing pancreatic islet-cell tumors is the presence of adjacent enhancing vessels. Because pancreatic islet-cell tumors are often intensely vascular, their appearance in the axial cross-section can either mimic, or be obscured by, adjacent vessels of similar caliber. 9 Multiplanar reformations as well as multiphasic imaging can be helpful to avoid this potential pitfall. Occasionally, hypervascular metastases to the pancreas can occur, most commonly from renal-cell carcinoma. While rare, these can be mistaken for a pancreatic islet-cell tumor due to similar enhancementcharacteristics.21

FIGURE 33. Response to chemotherapy. (A) Axial CT image shows several peripherally enhancing, centrally hypoattenuating liver masses and large hypodense pancreatic islet-cell tumor prior to chemotherapy. (B) Following chemotherapy, significant improvement with decrease in size of pancreatic-head mass as well as size of liver metastases. Majority of liver parenchyma returned to normal attenuation and enhancement pattern. A metallic biliary stent was placed in the interim.

tumors, multiple hypervascular pancreatic masses are often present (Figures 11 and 12). Additionally, other pancreatic lesions are commonly seen, such as multiple pancreatic cysts in patients with Von Hippel-Lindau syndrome (Figures 12and13). Metastatic lesions occurring in the liver are generally hypervascular in appearance on late arterial-phase scans, with similar enhancement characteristics as the primary pancreatic neoplasm

(Figure 14). Rapid washout from hepatic metastases may render them isodense on venous-phase acquisitions. It is therefore essential to perform arterial-phase imaging to detect liver metastases. As with the primary tumor, liver metastases can become centrally necrotic as they increase in size (Figure 15). Regional adenopathy, liver, bone and pulmonary metastases are additional imaging features of advanced disease (Figures 16 and17).

Atypicalimagingfindings
Atypical imaging appearances of pancreatic islet-cell tumors are not uncommon. While most islet-cell tumors are well-visualized on CT due to their hypervascular nature, some may be isoattenuating to the rest of the pancreas and challenging to visualize. In cases where the lesion is not immediately apparent, subtle pancreatic duct indentation or subtle changes in pancreatic duct caliber may be helpful clues

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in identifying the location of the lesion (Figure 18). Indeed, small isoattenuating lesions can be particularly difficult to delineate by CT and in some cases may be better seen on endoscopic ultrasound or intraoperativeultrasound. Another atypical appearance of isletcell tumors is that of cystic or necrotic change. Central necrosis is more commonly seen in larger nonsyndromic pancreatic islet-cell tumors that outgrow their blood supply. Often the lesion periphery will remain hypervascular while the center does not enhance (Figures 19 and 20).22 In our experience in one very rare instance, a pancreatic isletcell tumor presented with a purely cystic appearance(Figure21). Calcifications are not a typical imaging feature of pancreatic islet-cell tumors but can be seen in up to 20%, best delineated on CT (Figures 22 and 23). The presence of calcifications is more suggestive of a pancreatic islet-cell tumor and can be helpful in differentiating a lesion from adenocarcinomaofthepancreas.6 Vascular encasement, narrowing, and/or frank vascular invasion are aggressive findings commonly seen in pancreatic adenocarcinoma. Occasionally, these findings may also be seen with pancreatic islet-cell tumors. In these

atypical islet-cell tumors, the degree of vascular encasement or occlusion is often disproportionally less than that found in a similarly sized pancreatic adenocarcinoma (Figures 24-28). Beyond encasement, direct invasion of the portal vein with resulting tumor thrombus can rarely occur in islet-cell tumors, again mimicking an adenocarcinoma of the pancreas(Figure29). Another uncommon appearance of islet-cell tumors is pancreatic duct involvement. While mild mass effect upon the pancreatic duct is commonly seen, occasionally significant narrowing or pancreatic duct obstruction and subsequent dilatation can be present (Fig-ure 30). Obstruction may be so severe that intrahepatic biliary ductal dilatation may also be present (Figure 31). In these cases, the degree of obstruction is again usually lessthanwouldbeexpectedwithadenocarcinoma. Once the diagnosis and staging of a pancreatic islet-cell tumor is performed, imaging is helpful in determining the s u c c e s s o f s u rg i c a l t r e a t m e n t a n d monitoring for signs of recurrence. Recurrence may occur locally in the postoperative site, present as regional lymphadenopathy, or appear as distant metastatic disease in the liver, lungs or bone (Figure 32). Patients who are not

surgical candidates are also imaged to assessfortherapyresponse(Figure33).

Conclusion
The radiologist should be familiar with both typical and atypical imaging appearances of pancreatic islet-cell tumors and the appearance of metastatic disease to help determine whether a patient is a surgical candidate. The classic appearance of pancreatic islet-cell tumors is a solitary, well-circumscribed hypervascular lesion that does not disrupt the pancreatic duct. Advanced disease may present as regional adenopathy or distant metastases to liver, bone and/or lungs. Atypical appearances include isodense lesions, cystic change and internal calcifications. Rarely, islet-cell tumors may mimic a pancreatic adenocarcinoma by narrowing or obstructing the pancreatic duct or causing vascular encasement, occlusion orinvasion.

Acknowledgments
The authors wish to thank Jeslyn A. Rumboldforeditorialassistance.

REFERENCES
1. Kumar V AA, Fausto N. Robbins Basic Pathology. 8th Edition.Philadelphia:SaundersElsevier,2007. 2. Bartsch DK, Schilling T, Ramaswamy A, et al. Management of nonfunctioning islet cell carcinomas. WorldJSurg.2000;24:1418-1424. Actual # copies for September 2009 issue 23,693 12,197 12,197 10,907 200 11,107 23,304 389 23,693 52.3%

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