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Neuroendocrine Tumors of the Pancreas in von Hippel–Lindau Disease: Spectrum of Appearances at CT and MR Imaging with Histopathologic Comparison¹

¹ From the Department of Diagnostic Radiology (H.B.M., P.L.C.), Surgery Branch (S.K.L., H.R.A., D.L.B.), Urologic Oncology Branch (M.M.W., W.M.L., G.M.G., P.L.C.), Genetic Epidemiology Branch (G.M.G.), and Surgical Neurology Branch (I.A.L.), National Cancer Institute, National Institutes of Health, 10 Center Dr, MSC 1182, Bldg 10, Rm 1C660, Bethesda, MD 20892-1182. Received July 30, 2001; revision requested September 25; final revision received November 8; accepted May 14, 2002. Address correspondence to P.L.C. (e-mail: pchoyke@nih.gov).

	ABSTRACT

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PURPOSE: To demonstrate the imaging characteristics of neuroendocrine tumors (NETs) of the pancreas in patients with von Hippel–Lindau (VHL) disease to establish diagnostic criteria.

MATERIALS AND METHODS: Twenty-five patients with VHL disease and 29 surgically confirmed pancreatic NETs were included. Screening computed tomographic (CT) and/or magnetic resonance (MR) imaging findings were reviewed, and tumor number, diameter, growth rates (doubling time), location, presence of metastatic disease, and attenuation or enhancement properties were determined.

RESULTS: Eighteen of 29 (62%) pancreatic NETs were smaller than 3.0 cm in diameter and enhanced homogeneously on contrast material–enhanced CT and MR images. No tumor smaller than 3.0 cm metastasized. Tumors 3.0 cm or larger (11 [38%] of 29) more often enhanced heterogeneously, and two of 11 were associated with hepatic metastases. Smaller (<3.0 cm) tumors displayed longer mean doubling times (mean, 927 vs 351 days) than did larger (3.0 cm) tumors; however, there was considerable overlap. Fifteen (52%) tumors were located in the pancreatic head; eight (28%), in the tail; and six (21%), in the body. Ten (40%) patients with pancreatic NETs had associated pheochromocytomas, and 22 (88%) had no or mild pancreatic cystic disease, which is substantially more than the general population of patients with VHL disease.

CONCLUSION: Pancreatic NETs in VHL have characteristic features at CT and MR imaging: Most are small, located in the pancreatic head, and enhance homogeneously. Tumors larger than 3.0 cm are prone to metastasize and enhance heterogeneously.

© RSNA, 2002

Index terms: Pancreas, neoplasms, 770.3191 • Pancreas, CT, 770.12112, 771.12114 • Pancreas, cysts, 770.31 • Pancreas, MR, 770.121411, 770.121412, 770.1214, 770.121415, 770.12143 • Pheochromocytoma, 86.328 • von Hippel–Lindau disease, 770.1834

	INTRODUCTION

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Von Hippel–Lindau (VHL) disease is an autosomal-dominant heritable syndrome characterized by development of a variety of benign and malignant tumors in multiple organ systems, such as the brain, kidney, pancreas, adrenal gland, and epididymis. Hallmarks of the condition include retinal angiomas, hemangioblastomas of the cerebellum and spinal cord, renal cell carcinomas and cysts, pheochromocytomas, and benign and malignant tumors of the pancreas (1–4). The gene for VHL syndrome was identified in 1993 (5) and localized to chromosome 3p25.5.

A majority of pancreatic lesions in patients with VHL disease are cystic and benign. Pancreatic cystic clusters are histologically classified as serous cystadenomas (6). At computed tomography (CT), these cystic lesions typically do not enhance or enhance minimally after intravenous contrast material administration. At magnetic resonance (MR) imaging, they typically demonstrate high signal intensity on T2-weighted images, which is reflective of their cystic nature, and show a similar lack of enhancement on images obtained after gadolinium-based contrast material administration. However, solid neuroendocrine tumors (NETs) of the pancreas (formerly called islet cell tumors) have also been reported in VHL disease (7–12). These tumors differ from cystic lesions in that they can metastasize. Pancreatic NETs tend to grow slowly, are not hyperfunctional, and are, therefore, usually asymptomatic (3,12). Several small case series of pancreatic NETs (10–12) have been reported; however, to our knowledge, the full spectrum of imaging appearances of such tumors has not been described. This has led to decreased awareness of this manifestation of VHL disease, as compared with the others, and to confusion with pancreatic cystic disease. The purpose of our study was to demonstrate the imaging characteristics of pancreatic NETs in patients with VHL disease.

	MATERIALS AND METHODS

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Patients
An electronic database containing clinical and imaging data obtained in 450 patients with VHL disease between August 1990 and January 2001 was queried for data on patients with histologically confirmed pancreatic NETs. This revealed 25 patients with 29 lesions (15 women, 10 men; age range, 16–42 years; mean age, 31.7 years). All tumors had been identified at screening CT and/or MR imaging. All patients had been entered into an institutional review board–approved screening protocol. A signed informed consent form was obtained for each patient. Each patient underwent a comprehensive evaluation, including physical and clinical examination, laboratory testing, and gene mutation studies. All patients with VHL disease routinely underwent contrast-enhanced MR imaging of the head and spine and contrast-enhanced and nonenhanced CT of the abdomen. Eleven patients underwent contrast-enhanced MR imaging of the abdomen. Further investigations, including abdominal ultrasonography (US) (18 patients) and angiography (six patients), were also performed. MR imaging was performed in patients who had an allergic reaction to CT contrast material or in whom additional information was sought. All patients underwent intraoperative US. CT and MR imaging findings were compared with surgical and histopathologic findings in all patients.

Imaging Techniques
CT scanning.—CT was performed with a variety of scanners, since this study spans 10 years (model 9800, HiLight, and Light Speed; GE Medical Systems, Milwaukee, Wis). Nonionic iodinated contrast material (120–140 mL iopamidol, Isovue 300, Bracco Diagnostics, Princeton, NJ; or oxilan, Ioxilan 300, Cook, Bloomington, Ind) was injected intravenously at 1.5–2.0 mL/sec by using a power injector (Mark IV; Medrad, Pittsburgh, Pa). Scans were obtained with 5-mm collimation before and after contrast material administration. Acquisition was initiated 80 seconds after the start of contrast material injection. Scanning was delayed in five patients because of an adverse reaction to the contrast material. Concerns raised by the institutional review board about radiation exposure from repeated CT examinations led to performance of only one portal phase examination optimized for kidney evaluation instead of the preferred dual phase examination. Since fewer than 10% of patients with VHL disease have pancreatic NETs, and a considerable number of these patients are young adults, it was thought inappropriate to expose the majority of patients with VHL disease to additional radiation. Since the diagnosis could not be made a priori, dual phase CT was not performed in this study, even though it would have improved the diagnosis of NETs. The imaging protocol included follow-up at 6–12 months for at least 3 years if the patient elected to return.

MR imaging.—Fourteen of 25 patients also underwent abdominal MR imaging with one of several 1.5-T imagers (including Sigma Horizon; GE Medical Systems). The intravenously injected gadolinium-based contrast material was used in conjunction with a fat-suppressed breath-hold spoiled gradient-echo sequence in all cases. Spoiled gradient-echo imaging encompassed the pancreas in one or two breath holds. T1-weighted spoiled gradient-echo images were acquired before contrast material administration, with and without fat suppression in transverse and coronal planes, and T2-weighted fat-suppressed fast spin-echo or spin-echo images were also acquired in the transverse plane. Parameters for T1-weighted spoiled gradient-echo imaging were 140–170/1.6–4.1 (repetition time msec/echo time msec), a flip angle of 70°, one signal acquired, a section thickness of 7–10 mm, a matrix of 192 x 256, and 10–16 sections acquired in a 22–31-second breath hold. Parameters for T2-weighted fast spin-echo imaging were 5,700/126 and an echo train length of four to eight. Parameters for T2-weighted spin-echo imaging were 2,000/80. A gadolinium chelate (gadopentetate dimeglumine, Magnevist; Berlex, Wayne, NJ) was injected rapidly at a dose of 0.1 mmol per kilogram of body weight. Images were acquired immediately following contrast material administration during the hepatic arterial dominant phase. Additional acquisitions were at 90 and 180 seconds.

Image Interpretation and Data Analysis
CT and MR images were retrospectively evaluated by two readers in consensus (H.B.M., P.L.C.). The retrospective reviews were not blinded to the presence of pancreatic NETs. The number, size, growth rate (doubling time [DT]), presence of metastases, location, and pattern and degree of tumor enhancement on images obtained after contrast material administration were determined. DT was defined as the time required for a tumor to double in volume. Tumors were measured with calipers in three dimensions, and the mean diameter was calculated. Comparisons were made with available pathologic findings and with genetic analysis findings in all patients. Associated findings, such as cysts and solid masses in the kidneys and adrenal glands, pancreatic cysts, and hepatic metastases were also recorded. Findings on CT and MR images were compared separately with surgical findings provided at consultation with the surgeon (S.K.L., H.R.A., D.L.B.) and at review of surgery and pathology reports.

	RESULTS

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Of the 25 patients with surgically confirmed pancreatic NETs, four had two solid pancreatic lesions, for a total of 29 lesions. Eighteen (62%) of the 29 tumors were smaller than 3.0 cm (range, 0.5–2.9 cm), while the remaining 11 (38%) were 3.0 cm or larger (range, 3.0–7.0 cm). The smaller (<3.0-cm) tumors showed slower mean growth rates (mean DT, 927 days; range, 186–2,159 days), while higher mean growth rates were observed in larger (3.0-cm) tumors (mean DT, 351 days; range, 277–494 days); however, there was considerable overlap (Fig 1). Fewer larger lesions had serial measurements because they were often removed before long-term follow-up.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Graph illustrates findings of tumor size versus DT in the current study.

View larger version (106K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Transverse CT and MR images obtained in a 35-year-old woman with VHL syndrome and pancreatic NET. (a) Contrast-enhanced CT scan demonstrates a 2.0 x 1.8-cm mass in the pancreatic head (arrows) that is homogeneously enhancing. (b) T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) obtained by using a phased-array coil at the same tomographic location 7 months after a shows the same mass. The mass (arrows) is well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm). (c) Transverse T2-weighted fast spin-echo MR image (5,700/126) shows that the mass (arrows) is moderately high in signal intensity. (d) Early and (e) delayed postcontrast T1-weighted spoiled gradient-echo MR images with fat suppression (150/1.9; flip angle, 70°) show an intense homogeneous enhancement pattern in the mass (arrows) that remains higher in signal intensity than does background pancreatic tissue. This finding reflects the abundant blood supply of the tumor. (f) Histopathologic specimen from the resected tumor shows classic trabecular architecture (short arrow) and small NET cells (long arrow) with eosinophilic cytoplasm. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (115K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Transverse CT and MR images obtained in a 35-year-old woman with VHL syndrome and pancreatic NET. (a) Contrast-enhanced CT scan demonstrates a 2.0 x 1.8-cm mass in the pancreatic head (arrows) that is homogeneously enhancing. (b) T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) obtained by using a phased-array coil at the same tomographic location 7 months after a shows the same mass. The mass (arrows) is well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm). (c) Transverse T2-weighted fast spin-echo MR image (5,700/126) shows that the mass (arrows) is moderately high in signal intensity. (d) Early and (e) delayed postcontrast T1-weighted spoiled gradient-echo MR images with fat suppression (150/1.9; flip angle, 70°) show an intense homogeneous enhancement pattern in the mass (arrows) that remains higher in signal intensity than does background pancreatic tissue. This finding reflects the abundant blood supply of the tumor. (f) Histopathologic specimen from the resected tumor shows classic trabecular architecture (short arrow) and small NET cells (long arrow) with eosinophilic cytoplasm. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (115K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. Transverse CT and MR images obtained in a 35-year-old woman with VHL syndrome and pancreatic NET. (a) Contrast-enhanced CT scan demonstrates a 2.0 x 1.8-cm mass in the pancreatic head (arrows) that is homogeneously enhancing. (b) T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) obtained by using a phased-array coil at the same tomographic location 7 months after a shows the same mass. The mass (arrows) is well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm). (c) Transverse T2-weighted fast spin-echo MR image (5,700/126) shows that the mass (arrows) is moderately high in signal intensity. (d) Early and (e) delayed postcontrast T1-weighted spoiled gradient-echo MR images with fat suppression (150/1.9; flip angle, 70°) show an intense homogeneous enhancement pattern in the mass (arrows) that remains higher in signal intensity than does background pancreatic tissue. This finding reflects the abundant blood supply of the tumor. (f) Histopathologic specimen from the resected tumor shows classic trabecular architecture (short arrow) and small NET cells (long arrow) with eosinophilic cytoplasm. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 2d. Transverse CT and MR images obtained in a 35-year-old woman with VHL syndrome and pancreatic NET. (a) Contrast-enhanced CT scan demonstrates a 2.0 x 1.8-cm mass in the pancreatic head (arrows) that is homogeneously enhancing. (b) T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) obtained by using a phased-array coil at the same tomographic location 7 months after a shows the same mass. The mass (arrows) is well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm). (c) Transverse T2-weighted fast spin-echo MR image (5,700/126) shows that the mass (arrows) is moderately high in signal intensity. (d) Early and (e) delayed postcontrast T1-weighted spoiled gradient-echo MR images with fat suppression (150/1.9; flip angle, 70°) show an intense homogeneous enhancement pattern in the mass (arrows) that remains higher in signal intensity than does background pancreatic tissue. This finding reflects the abundant blood supply of the tumor. (f) Histopathologic specimen from the resected tumor shows classic trabecular architecture (short arrow) and small NET cells (long arrow) with eosinophilic cytoplasm. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (98K): [in this window] [in a new window] [Download PPT slide]   Figure 2e. Transverse CT and MR images obtained in a 35-year-old woman with VHL syndrome and pancreatic NET. (a) Contrast-enhanced CT scan demonstrates a 2.0 x 1.8-cm mass in the pancreatic head (arrows) that is homogeneously enhancing. (b) T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) obtained by using a phased-array coil at the same tomographic location 7 months after a shows the same mass. The mass (arrows) is well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm). (c) Transverse T2-weighted fast spin-echo MR image (5,700/126) shows that the mass (arrows) is moderately high in signal intensity. (d) Early and (e) delayed postcontrast T1-weighted spoiled gradient-echo MR images with fat suppression (150/1.9; flip angle, 70°) show an intense homogeneous enhancement pattern in the mass (arrows) that remains higher in signal intensity than does background pancreatic tissue. This finding reflects the abundant blood supply of the tumor. (f) Histopathologic specimen from the resected tumor shows classic trabecular architecture (short arrow) and small NET cells (long arrow) with eosinophilic cytoplasm. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Figure 2f. Transverse CT and MR images obtained in a 35-year-old woman with VHL syndrome and pancreatic NET. (a) Contrast-enhanced CT scan demonstrates a 2.0 x 1.8-cm mass in the pancreatic head (arrows) that is homogeneously enhancing. (b) T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) obtained by using a phased-array coil at the same tomographic location 7 months after a shows the same mass. The mass (arrows) is well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm). (c) Transverse T2-weighted fast spin-echo MR image (5,700/126) shows that the mass (arrows) is moderately high in signal intensity. (d) Early and (e) delayed postcontrast T1-weighted spoiled gradient-echo MR images with fat suppression (150/1.9; flip angle, 70°) show an intense homogeneous enhancement pattern in the mass (arrows) that remains higher in signal intensity than does background pancreatic tissue. This finding reflects the abundant blood supply of the tumor. (f) Histopathologic specimen from the resected tumor shows classic trabecular architecture (short arrow) and small NET cells (long arrow) with eosinophilic cytoplasm. (Hematoxylin-eosin stain; original magnification, x400.)

View larger version (115K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. Transverse contrast-enhanced CT scans obtained in a 21-year-old woman with VHL syndrome and an enhancing uncinate-process mass that is growing slowly. (a) CT scan shows a 1.3 x 1.5-cm homogeneously enhancing mass in the uncinate process (arrows). (b) CT scan obtained 2 years after a shows only slight growth of the mass (1.5 x 1.7 cm; DT, 638 days).

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. Transverse contrast-enhanced CT scans obtained in a 21-year-old woman with VHL syndrome and an enhancing uncinate-process mass that is growing slowly. (a) CT scan shows a 1.3 x 1.5-cm homogeneously enhancing mass in the uncinate process (arrows). (b) CT scan obtained 2 years after a shows only slight growth of the mass (1.5 x 1.7 cm; DT, 638 days).

View larger version (101K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. Images obtained in a 39-year-old woman with VHL syndrome and "occult" NET. (a) Transverse contrast-enhanced CT scan acquired during the equilibrium phase shows no identifiable mass in the pancreatic head. Acquisition of this scan was delayed from the time of injection. (b) Transverse contrast-enhanced arterial phase T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) shows homogeneous enhancement of the 2.0-cm mass (arrows). (c) Histopathologic specimen from the resected tumor shows solid architecture, small vessels (short arrows), and cells with prominent clear cytoplasm (long arrow). (Hematoxylin-eosin stain; original magnification, x400.) At gross examination, this tumor demonstrated prominent yellow coloring secondary to abundant lipid content.

View larger version (88K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. Images obtained in a 39-year-old woman with VHL syndrome and "occult" NET. (a) Transverse contrast-enhanced CT scan acquired during the equilibrium phase shows no identifiable mass in the pancreatic head. Acquisition of this scan was delayed from the time of injection. (b) Transverse contrast-enhanced arterial phase T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) shows homogeneous enhancement of the 2.0-cm mass (arrows). (c) Histopathologic specimen from the resected tumor shows solid architecture, small vessels (short arrows), and cells with prominent clear cytoplasm (long arrow). (Hematoxylin-eosin stain; original magnification, x400.) At gross examination, this tumor demonstrated prominent yellow coloring secondary to abundant lipid content.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 4c. Images obtained in a 39-year-old woman with VHL syndrome and "occult" NET. (a) Transverse contrast-enhanced CT scan acquired during the equilibrium phase shows no identifiable mass in the pancreatic head. Acquisition of this scan was delayed from the time of injection. (b) Transverse contrast-enhanced arterial phase T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) shows homogeneous enhancement of the 2.0-cm mass (arrows). (c) Histopathologic specimen from the resected tumor shows solid architecture, small vessels (short arrows), and cells with prominent clear cytoplasm (long arrow). (Hematoxylin-eosin stain; original magnification, x400.) At gross examination, this tumor demonstrated prominent yellow coloring secondary to abundant lipid content.

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Transverse contrast-enhanced CT scan obtained in a 31-year-old man with VHL syndrome who had a pancreatic mass and hepatic metastases at presentation. The scan shows an ill-defined 6.0 x 4.0-cm mass (long arrows) at the midbody of the pancreas that resulted in encasement of the superior mesenteric artery and vein and splenic artery. The mass is enhancing heterogeneously. Multiple hypervascular enhancing focal hepatic metastases (short solid arrow indicates one) are also seen. Note the left adrenal mass (pheochromocytoma) (open arrow). The patient underwent surgical removal of the pheochromocytoma and hepatic biopsy for hepatic metastasis.

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 6a. Transverse T1-weighted spoiled gradient-echo MR images with fat suppression obtained in a 32-year-old woman with VHL syndrome that manifested as a large mass in the pancreatic tail and as hepatic metastases. (a) Precontrast MR image (150/1.9; flip angle, 70°) demonstrates an ill-defined heterogeneous mass with low signal intensity (short arrows) that measures 4.5 x 3.0 cm and is located in the pancreatic tail, slightly medial and posterior to the posterior gastric wall. Two focal low-signal-intensity masses (long arrows) are seen in the right and left lobes of the liver. (b) Postcontrast MR image (150/1.9; flip angle, 70°) obtained 90 seconds after injection and at the same tomographic location as a shows the mass (short arrows) enhancing heterogeneously. The tumor heterogeneity seen on the pre- and postcontrast images is consistent with necrosis. Hypervascular hepatic metastases (long arrows) are also noted. On the 4-month follow-up MR image (not shown), the tumor showed a size increase that reflected a higher growth rate (DT, 277 days). The patient underwent distal pancreatectomy and radio-frequency thermal ablation of hepatic metastases. Histopathologic examination of the resected tumor showed features similar to those described for the tumors smaller than 3.0 cm. However, malignant microscopic infiltration of adjacent organs and hepatic metastases were identified.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 6b. Transverse T1-weighted spoiled gradient-echo MR images with fat suppression obtained in a 32-year-old woman with VHL syndrome that manifested as a large mass in the pancreatic tail and as hepatic metastases. (a) Precontrast MR image (150/1.9; flip angle, 70°) demonstrates an ill-defined heterogeneous mass with low signal intensity (short arrows) that measures 4.5 x 3.0 cm and is located in the pancreatic tail, slightly medial and posterior to the posterior gastric wall. Two focal low-signal-intensity masses (long arrows) are seen in the right and left lobes of the liver. (b) Postcontrast MR image (150/1.9; flip angle, 70°) obtained 90 seconds after injection and at the same tomographic location as a shows the mass (short arrows) enhancing heterogeneously. The tumor heterogeneity seen on the pre- and postcontrast images is consistent with necrosis. Hypervascular hepatic metastases (long arrows) are also noted. On the 4-month follow-up MR image (not shown), the tumor showed a size increase that reflected a higher growth rate (DT, 277 days). The patient underwent distal pancreatectomy and radio-frequency thermal ablation of hepatic metastases. Histopathologic examination of the resected tumor showed features similar to those described for the tumors smaller than 3.0 cm. However, malignant microscopic infiltration of adjacent organs and hepatic metastases were identified.

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 7a. Transverse CT and MR images obtained in a 23-year-old woman with VHL syndrome that manifested as a 4.0-cm mass in the pancreatic tail. (a) Transverse contrast-enhanced CT scan shows a 4.0 x 3.2-cm mass with ill-defined margins (thick arrows) in the pancreatic tail. The mass enhances heterogeneously, with multiple areas of calcification (thin arrow). (b) Early postcontrast T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) shows the mass (thick arrows) enhancing heterogeneously, with a central signal void in the calcification (thin arrow). The patient underwent distal pancreatectomy.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 7b. Transverse CT and MR images obtained in a 23-year-old woman with VHL syndrome that manifested as a 4.0-cm mass in the pancreatic tail. (a) Transverse contrast-enhanced CT scan shows a 4.0 x 3.2-cm mass with ill-defined margins (thick arrows) in the pancreatic tail. The mass enhances heterogeneously, with multiple areas of calcification (thin arrow). (b) Early postcontrast T1-weighted spoiled gradient-echo MR image with fat suppression (150/1.9; flip angle, 70°) shows the mass (thick arrows) enhancing heterogeneously, with a central signal void in the calcification (thin arrow). The patient underwent distal pancreatectomy.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 8. Drawing illustrates the location and size of pancreatic NETs in the current study. Dotted lesions are tumors associated with hepatic metastases.

The 18 smaller tumors enhanced homogeneously, while the 11 larger tumors tended to enhance heterogeneously after contrast material administration during the arterial and portal venous phases on CT and MR images (Figs 6, 7). No tumor smaller than 3.0 cm in diameter metastasized to the liver. Two of the 11 larger (3.0-cm) tumors metastasized to the liver. The two patients with hepatic metastases underwent hepatic biopsy for confirmation of their disease. Central necrosis was present in three tumors. However, cystic lesions were easily distinguished from necrotic pancreatic NETs, since the former demonstrated minimal thin peripheral enhancement, while the latter demonstrated thick-walled enhancement. All lesions demonstrated at CT (with the exception of those in a patient who developed an allergic reaction and whose CT examination was thus delayed) were confirmed with dynamic contrast-enhanced MR imaging.

There was an association between pancreatic NETs and pheochromocytomas. Ten (40%) of the 25 patients also had surgically confirmed adrenal pheochromocytomas.

Conversely, despite the high prevalence of pancreatic cystic disease in the general population of patients with VHL disease in this study (approximately 60% of patients with VHL disease had moderate to severe cystic disease of the pancreas), only three (12%) of 25 patients with pancreatic NETs showed severe cystic pancreatic disease accompanying the solid lesions; in 11 patients, there were no cysts; and in the other 11 patients, the cystic disease was mild (1–10 cysts in the pancreas). Thus, pancreatic NETs were usually found in patients with an otherwise normal pancreas or only mild pancreatic cystic disease.

With regard to renal evaluation, solid renal tumors were found and confirmed to be renal cancer in 13 patients. Cystic renal disease was found in 10 patients. The remaining two patients had no renal abnormalities.

CT and MR imaging findings were compared with surgical and histopathologic findings in all 25 patients. Intraoperative US was performed in all patients and depicted the tumor in all. Surgical interventions included enucleation (11 patients), distal pancreatectomy (eight patients), the Whipple procedure (five patients), and hepatic biopsy (one patient). Histologic analysis of surgically removed tumors demonstrated trabeculae and solid architecture characteristic of NET. The diagnosis was confirmed with positive findings of immunohistochemical staining with chromagranin A and synaptophasin. Negative findings of immunostaining for pancreatic and gastrointestinal hormones was observed in 66% (19 of 29 tumors) of the total, and staining findings were positive for pancreatic polypeptide, somatostatin, insulin, and/or glucagon in 34% (10 of 29 tumors). There were no distinguishing histologic features between tumors of varying size. However, three of the 11 larger tumors demonstrated areas of necrosis at histologic examination.

Histologic malignant microscopic infiltration of the adjacent peripancreatic tissues was observed in the two patients with hepatic metastases. The liver was the only site of distant metastasis in these patients.

Genetic mutation analysis demonstrated missense mutations (13 [52%] patients), partial deletion mutations (four [16%] patients), nonsense mutations (four [16%] patients), frameshift mutations (two [8%] patients), deletion (one [4%] patient), and a splice donor mutation (one [4%] patient). There was no association of a specific mutation with metastasis. These results are summarized in the Table.

	DISCUSSION

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A majority (62%) of the lesions in this study were smaller than 3.0 cm in diameter and demonstrated very long DTs (mean, 927 days) that were reflective of slow growth. A common experience is that these lesions remain radiologically stable over a period of years or grow very slowly (3,7,8). Mean DTs were longer in smaller (<3.0-cm) tumors. While some of these lesions will metastasize, the probability is low. For this reason, they may be observed rather than immediately removed. Their removal can therefore be coordinated with surgery required for other lesions (eg, pheochromocytomas or renal cancers), thus sparing the patient from undergoing multiple surgical procedures. However, not all pancreatic NETs were equivalently indolent in behavior. Indeed, almost 20% of lesions 3.0 cm in diameter or larger had metastasized to the liver. Thus, while a majority of pancreatic NETs are small and benign, a minority can progress to metastatic disease. Active surveillance for these lesions is therefore justified.

Pancreatic NETs were not uniformly distributed throughout the pancreas. Over half (52%) of these lesions were located in the pancreatic head, even though the head accounts for only about one-third of the pancreatic volume. This raises the possibility that the pancreatic head is predisposed to development of pancreatic NETs in patients with VHL disease. The pancreatic head differs from the remainder of the pancreas in that it arises from the ventral pancreatic anlage and has been shown to contain a higher proportion of polypeptide cells, as compared with the remainder of the pancreas (15–17). Whether or not the environment of the pancreatic head is predisposed to development of pancreatic NETs in patients with VHL disease remains conjectural.

Pancreatic NETs are hypervascular. This reflects a rich capillary network within these tumors. As a consequence, imaging is best performed early after the bolus of contrast material is injected, whether at CT or at MR imaging. Tumor enhancement was homogeneous in tumors smaller than 3.0 cm; however, heterogeneous enhancement was more common in lesions larger than 3.0 cm (9). It is possible that vascular heterogeneity may be a sign of malignant transformation, since malignancies are often heterogeneous in vascular structure, perfusion, and vascular permeability (18). As tumors grow, the central portions become less vascularized. Calcifications and necrosis can be seen. The latter can superficially mimic a typical serous cystadenoma of the pancreas but is usually distinguished by the thick, irregularly enhancing rim of tumor (4).

Several observations suggest a unique genetic mechanism for pancreatic NETs in patients with VHL disease. For instance, moderate to severe pancreatic cystic disease, which occurs in approximately 40%–60% of the overall population of patients with VHL disease (6), is relatively uncommon in patients with VHL disease who have NETs (three [12%] of 25), according to our study findings. This suggests that NETs and serous cystadenomas may have different developmental pathways and thus represent independent lesions. An association with pheochromocytomas (40% of patients with pancreatic NETs in the current study) is further evidence of a unique pathway of development (10). The concept that these tumors arise either from pancreatic neuroendocrine cells, which are believed to be derived from the neural crest (15), or from a single neuroendocrine-programmed ectoblast (19) raises the possibility that these tumors share a common origin with pheochromocytomas. Pancreatic NETs and pheochromocytomas are associated with missense mutations of the VHL gene, as opposed to other mutation types. However, there are exceptions to all of these observations that indicate that tumor development in patients with VHL disease is a complex and multifactorial process.

Pancreatic NETs are generally treated by using pancreas-sparing surgical procedures. Lesions in the tail of the pancreas can be treated with distal pancreatectomy, whereas small lesions in the pancreatic head can be treated with enucleation (7,9). Larger lesions require more aggressive surgery, including the Whipple procedure (9). When possible, pancreas-sparing surgery should be performed to minimize morbidity, including pancreatic exocrine and endocrine insufficiency. At our institution, we have adopted a conservative approach and have opted to follow up patients with small pancreatic NETs, often combining surgery on other organs (the adrenal gland or kidney) with pancreatic resection. This strategy decreases the number of surgical interventions that patients with VHL disease must undergo and maximally preserves pancreatic function.

The findings of our study are limited by the relatively small number of patients, which reflects the rarity of these tumors. A larger multiinstitutional study is required to definitively confirm the characteristic imaging features of these tumors. Further, the patients in this study were highly selected for the more severe cases of pancreatic NET (and, thus may not represent the entire spectrum of this disease because they underwent surgery, whereas many other patients were simply followed up) for the more severe cases of pancreatic NET because they underwent surgery (verification bias). However, we are currently following up an additional 15 patients suspected of having pancreatic NETs, and the observations have been the same with regard to tumor size, enhancement patterns, and growth rates. Another limitation of the study was that dual phase CT was not performed. This was due to a conscious effort to reduce ionizing radiation exposure in this tumor-prone population. Another limitation was that the two readers reviewed the images in consensus, so interobserver variability could not be evaluated. Finally, an unavoidable limitation was the substantial change in computer hardware and software that occurred over the 10 years of this study.

In summary, pancreatic NETs in VHL disease have characteristic features at CT and MR imaging: Most are small, located in the pancreatic head, and enhance homogeneously. However, a minority of lesions are large, heterogeneously enhancing, demonstrate more aggressive growth, and can metastasize to the liver. The propensity of pancreatic lesions to be located in the pancreatic head, their association with pheochromocytomas, and their lack of association with pancreatic serous cystadenomas raise intriguing questions regarding the origin of the lesions. The available CT and MR imaging techniques may help to diagnose and follow up these lesions and provide the opportunity to perform pancreas-sparing procedures when necessary.

	FOOTNOTES

 
Abbreviations: DT = doubling time, NET = neuroendocrine tumor, VHL = von Hippel–Lindau

Author contributions: Guarantors of integrity of entire study, H.B.M., P.L.C.; study concepts and design, H.B.M., P.L.C.; literature research, H.B.M.; clinical studies, P.L.C., S.K.L.; data acquisition and analysis/interpretation, H.B.M., P.L.C.; statistical analysis, P.L.C., H.B.M.; manuscript preparation, definition of intellectual content, and editing, H.B.M., P.L.C.; manuscript revision/review, all authors; manuscript final version approval, H.B.M., P.L.C.

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