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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Alexis Lacout, MD Jean-Pierre Pelage, MD, PhD Gilles Lesur, MD Thierry Chinet, MD Alain Beauchet, MD Joëlle Roume, MD Pascal Lacombe, MD Pancreatic Involvement in Hereditary Hemorrhagic Telangiectasia: Assessment with Multidetector Helical CT 1 Purpose: Materials and Methods: To evaluate and describe pancreatic involvement by using multidetector computed tomography (CT) in patients with a diagnosis of hereditary hemorrhagic telangiectasia (HHT). Institutional review board approval was obtained, and all patients provided informed consent. Across 12 months, all consecutive adult patients with a confirmed diagnosis of HHT referred to our pluridisciplinary HHT center for evaluation were enrolled prospectively in the study and underwent contrast material enhanced multidetector CT of the abdomen. Pancreatic telangiectases and arteriovenous fistulas were noted, and their characteristics were described. Genetic mutation was also investigated. ORIGINAL RESEARCH n GASTROINTESTINAL IMAGING Results: Thirty-five patients (19 women, 16 men; mean age, 48.4 years) were included. All patients were asymptomatic. A genetic mutation was identified in 28 (80%) patients, including endoglin in 16 (57%), activin type-ii-like receptor kinase 1 ( ALK1 ) in 11 (39%), and SMAD4 in one (4%). Eleven (31%) patients exhibited pancreatic involvement. Fifty-four percent of patients with ALK1 mutation had pancreatic involvement. Twenty-three pancreatic telangiectases were identified during the arterial phase in nine patients. Seven pancreatic arteriovenous malformations (AVMs) were identified in four patients. Conclusion: Pancreatic involvement commonly is found in patients with HHT (31% in our study), mainly in patients with ALK1 mutation; pancreatic telangiectases or AVMs are only diagnosed during the arterial phase at multidetector CT. q RSNA, From the Departments of Radiology (A.L., J.P.P., P.L.), Hepatogastroenterology (G.L.), Pulmonology (T.C.), Statistics and Public Health (A.B.), and Genetics (J.R.), Pluridisciplinary HHT Center, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, 9, avenue Charles de Gaulle, Boulogne CEDEX, France. Received January 15, 2009; revision requested February 23; fi nal revision received June 23; accepted July 23; fi nal version accepted August 25. Address correspondence to J.P.P. ( jean-pierre. pelage@apr.aphp.fr ). q RSNA, 2010 Radiology: Volume 254: Number 2 February 2010 n radiology.rsna.org 479

2 Also known as Osler-Weber-Rendu syndrome, hereditary hemorrhagic telangiectasia (HHT) is a condition transmitted in an autosomal dominant pattern and characterized by arteriovenous malformations (AVMs) in the skin, mucous membranes, and visceral organs ( 1 4 ). There are two types of HHT, types l and 2, caused by mutations in the endoglin and activin type-ii-like receptor kinase 1 ( ALK1 ) genes, respectively ( 4 ). The endoglin and ALK1 genes code for proteins that are involved in proper blood vessel development. HHT has variable expression in affected members of a family ( 4 ). Mild to moderate epistaxis is the most common symptom of HHT ( 2,4 ). To permit a high degree of clinical suspicion, recent international consensus diagnostic criteria have been developed on the basis of four criteria: spontaneous recurrent epistaxis, mucocutaneous telangiectasia, visceral involvement (including pulmonary AVMs and hepatic, cerebral, or spinal AVMs), and a firstdegree relative affected by HHT ( 3 ). Penetrance is age related and is nearly complete by the age of 40 ( 4 ). Common symptoms in older adults include frequent epistaxis and, less commonly, gastrointestinal bleeding ( 1,4 ). A substantial proportion of patients with HHT may be affected by hepatic disease, which can cause symptoms such as heart failure, abdominal pain, abnormal hepatic function test results, or even pseudocirrhosis ( 5 ). Hepatic involvement has been studied extensively with Doppler ultrasonog- Advances in Knowledge n Pancreatic involvement is common and asymptomatic in adult patients with a confirmed diagnosis of hereditary hemorrhagic telangiectasia (HHT). n The majority of patients with activin type-ii-like receptor kinase 1 mutation in our series had pancreatic involvement. n Pancreatic telangiectasia or arte- riovenous malformations are imaged optimally during arterial phase multidetector CT. raphy (US) and more recently with helical multidetector computed tomography (CT) ( 6 8 ). Multidetector CT has the ability to depict both parenchymal involvement (telangiectasias and large confluent vascular masses) and the different types of intrahepatic vascular shunts (arteriosystemic, arterioportal, and portosystemic) ( 8,9 ). Multidetector CT could be the best imaging modality for detecting hepatic involvement, principally because of its good spatial resolution and the possibility of a multiphase study of the parenchyma after intravenous injection of iodinated contrast material ( 9 ). Conversely, pancreatic involvement in HHT has been evaluated poorly, except when angiography was used as a diagnostic modality ( 10,11 ). Given the high sensitivity reported for multidetector CT for the detection of hepatic involvement in HHT, we decided to evaluate pancreatic involvement in HHT by using multidetector CT. The purpose of our study was to evaluate and describe pancreatic involvement by using multidetector CT in patients with a diagnosis of HHT. Materials and Methods Patients Across 12 months, all consecutive adult patients with HHT referred to our pluridisciplinary HHT center (Hôpital Ambroise Paré, Boulogne, France ) for evaluation of their disease were enrolled prospectively in the study and underwent contrast material enhanced multidetector CT of the abdomen. Institutional review board approval was obtained, and all patients provided informed consent. According to the Curaçao clinical criteria, all patients met at least three of the four diagnostic criteria: family history of HHT, recurrent epistaxis, mucocutaneous telangiectases, and visceral involvement other Implication for Patient Care n Although asymptomatic, pancre- atic involvement by HHT can be identified at multidetector CT and may exist in the absence of other visceral involvement. than that of the pancreas (ie, pulmonary, hepatic, gastrointestinal, or cerebral involvement) ( 3 ). Children, patients declining to participate in the protocol, those with contraindication to intravenous administration of iodinated contrast material (known allergy or severe renal failure), and those with insufficient contrast material enhancement to look for vascular lesions were excluded from the study. Genetic mutation also was assessed, with emphasis on the three more commonly encountered in patients with HHT (ie, endoglin, ALK1, and SMAD4 ). Imaging All examinations were performed by using a 16 detector row helical CT scanner (Mx 8000 IDT; Philips Healthcare, Best, the Netherlands). Multiphasic multidetector CT examinations were performed through the region of clinical interest with the patients in the supine position. Thoracoabdominal evaluation was performed, from the cervicothoracic junction to the lower margin of the kidneys, with an early arterial phase, starting 35 seconds after intravenous injection of iodinated contrast material, with the following parameters: section thickness of 1 mm, pitch of 1.25, increment of 1 mm, rotation time of 0.5 second, 120 kv, and 150 mas. After the arterial phase, abdominopelvic evaluation was performed, from the hepatic dome to the lower margin of the kidneys, for Published online /radiol Radiology 2010; 254: Abbreviations: ALK1 = activin type-ii-like receptor kinase 1 AVM = arteriovenous malformation HHT = hereditary hemorrhagic telangiectasia Author contributions: Guarantors of integrity of entire study, J.P.P., G.L., J.R., P.L.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript fi nal version approval, all authors; literature research, A.L., J.P.P., G.L., J.R., P.L.; clinical studies, A.L., J.P.P., G.L., T.C., J.R., P.L.; statistical analysis, A.B.; and manuscript editing, all authors Authors stated no fi nancial relationship to disclose. 480 radiology.rsna.org n Radiology: Volume 254: Number 2 February 2010

3 A total of 35 patients (19 women, 16 men; mean age, 48.4 years ; age range, years) with a diagnosis of HHT (at least three Curaçao criteria) were included. All patients were without pancreatic symptoms, including abdominal pain, nausea, jaundice, or elevated lipase level. Three patients were excluded from the study because of contraindication for administration of iodinated contrast material. Six adthe portal phase, starting 80 seconds after intravenous injection of iodinated contrast material, with the following parameters: section thickness of 2.5 mm, pitch of 2, increment of 2 mm, rotation time of 0.5 second, 120 kv, and 200 mas. Nonionic contrast material (iohexol, Omnipaque 350; GE Healthcare, Vélizy- Villacoublay, France ) was injected into the antecubital vein through a gauge needle. We used an automatic injector (Injectron CT2; Medtron, Saarbrücken, Germany) and the following parameters: 1.5 ml per kilogram of body weight at a flow rate of 3 ml/sec with a maximum volume of 150 ml. Gastrointestinal contrast material (iodinated contrast material or water) was not administered. Image Evaluation The acquired data were transferred to a dedicated workstation (Extended Brilliance Workspace; Philips Healthcare). For the assessment of pancreatic involvement, we used axial reconstructions first. Additional multiplanar reformation and maximum intensity projection images also were obtained. Two radiologists (A.L., J.P.P.) with 4 and 10 years of experience, respectively, in abdominal and vascular imaging who were blinded to clinical data reviewed the original images and reconstructions on the workstation and made a consensual interpretation. The following criteria derived from published findings of hepatic involvement by HHT were applied to the pancreas and were evaluated during the arterial and the portal phases ( 1,2,4 ): presence of highly enhancing lesions compared with adjacent pancreatic parenchyma considered parenchymal pancreatic telangiectases; number, location (uncinate process, head, body, or tail in the pancreas), and size (largest diameter measured on axial images) of telangiectases; and presence and location of arteriovenous fistulas (characterized by an enlarged feeding artery connected to a draining vein). The diameter of the nidus between the feeding artery and draining vein was measured where possible. Patients with pancreatic telangi- ectases and/or arteriovenous fistulas were considered to have pancreatic involvement associated with HHT. Additional criteria suggesting pancreatic disease such as cysts, calcifications, or peripancreatic infiltration were also evaluated. Dilatation of the duct of Wirsung was noted (dilatation defined as. 3 mm in the corporeal and. 4 mm in the cephalic region). To reduce radiation exposure, we performed no scanning without intravenous administration of contrast material; calcifications were diagnosed in case of high-attenuation (. 500 HU) well-limited lesions, with no modification of attenuation and shape between the arterial phase and the portal phase. The diameter of the splenic artery also was measured to look for increased diameter in patients with pancreatic involvement. Pulmonary involvement (identification of pulmonary AVMs) and hepatic involvement (dilatation of the hepatic artery. 6 mm, telangiectases, or vascular confluent masses or intrahepatic vascular shunts) also were recorded carefully. Statistical Analysis Quantitative data were expressed as means 6 standard deviations with ranges. Qualitative data were expressed as frequency and percentage. Given the small sample size, frequencies were compared by using the Fisher exact test when necessary. A P value less than.05 was considered to indicate a statistically significant difference. We analyzed results by using commercially available software (SAS, version 9.1; SAS Institute, Cary, NC). Results ditional patients were excluded from final analysis because of suboptimal vascular enhancement precluding further analysis. Genetic mutation was identified in 28 (80%) of the 35 patients, including endoglin in 16 (57%), ALK1 in 11 (39%), and SMAD4 in one (4%) of the 28 patients. In six patients, no mutation was found, and the results were not available yet in one patient. Among the 35 patients, 11 (31%) had pancreatic involvement on the basis of the defined imaging criteria. Considering the 27 patients with endoglin or ALK1 genetic mutation, six (54%) of 11 patients with ALK1 mutation had pancreatic involvement versus two (13%) of 16 with endoglin mutation ( P =.09). Twenty-three pancreatic telangiectases were identified in nine (26%) of 35 patients ( Figs 1 3 ). All telangiectases were seen only during the arterial phase. The average number of pancreatic telangiectases was 2.6 per patient (range, 1 9), with five patients presenting with multiple lesions ( Fig 1 ). The mean diameter of the telangiectases was 4.1 mm (range, mm). Fifteen telangiectases (65%) were located in the body of the pancreas; seven (30%), in the head; and one (5 %), in the tail. Seven pancreatic AVMs were identified in four (11%) of 35 patients. The average diameter of the AVMs was 5.7 mm ( Fig 3 ). Of the 35 patients, seven (20%) had only telangiectases, two (6%) had telangiectases and AVMs, and two (6%) had only AVMs. One patient had telangiectases and multiple calcifications (previous history of pancreatitis) located in the head of the pancreas. No telangiectases or AVMs were visible during the portal phase, and no other pancreatic abnormality, including dilatation of the duct of Wirsung, was detected. The average diameter of the splenic artery was 4.8 mm (range, mm). There was a trend toward larger diameter in patients with pancreatic AVMs ( P =.08). One patient with a large (3.8 cm in diameter) splenic arterial aneurysm underwent diagnostic angiography of Radiology: Volume 254: Number 2 February 2010 n radiology.rsna.org 481

4 Figure 1 Figure 2 Figure 1: Multidetector CT image (multiplanar coronal maximum intensity projection reconstruction) in 59-year-old woman with HHT demonstrates multiple telangiectases (arrows) involving the head and tail of the pancreas. Figure 3 Figure 3: Multidetector CT image (multiplanar coronal maximum intensity projection reconstruction) in 61-year-old man with HHT demonstrates an AVM (arrow) involving the tail of the pancreas. The feeding artery and the aneurismal sac are identifi ed. the celiac and splenic arteries followed by superselective embolization of the aneurysm with coils ( Fig 2 ). During angiography, a pancreatic AVM was confirmed. Visceral involvement (pulmonary or hepatic lesions) was found in 31 (89%) of 35 patients; hepatic involvement, in 25 patients (71%); and pulmonary involvement, in 29 patients (83%). One patient with pancreatic involvement had no other visceral involvement. No correlation was found between the presence of pancreatic telangiectases or AVMs and the presence of hepatic or pulmonary involvement. Figure 2: Images in 61-year-old man with HHT. (a) Multidetector CT image (axial maximum intensity projection reconstruction) demonstrates a single pancreatic telangiectasia (arrowhead). A large splenic arterial aneurysm also is identifi ed. (b) Selective angiographic image of the splenic artery (right anterior oblique projection) obtained at the time of aneurysm embolization with multiple coils shows that the telangiectasia identifi ed at CT corresponds to an AVM (arrowhead). Discussion HHT is diagnosed on the basis of the Curaçao criteria established by the scientific advisory board of the HHT Foundation International ( 3 ). Diagnosis is based on a combination of clinical and anamnestic findings: (a) multiple mucocutaneous telangiectases at characteristic sites (lips, oral cavity, fingers, nose); (b) epistaxis, defined as spontaneous and recurrent episodes of nosebleeds; (c) visceral involvement, such as gastrointestinal telangiectases or pulmonary, 482 radiology.rsna.org n Radiology: Volume 254: Number 2 February 2010

5 hepatic, cerebral, or spinal AVM; and (d) a family history, defined as a firstdegree relative with HHT ( 3 ). Three criteria indicate a definitive diagnosis of the disorder in adults, and two criteria indicate a possible diagnosis ( 3 ). The most commonly affected visceral organs are the lung, brain, spinal cord, and liver ( 4 ). To our knowledge, pancreatic involvement by HHT has been evaluated poorly. Investigators ( 10,11 ) in two angiographic studies performed in five patients affected with or suspected of having HHT reported pancreatic telangiectases. In these angiographic studies, the characteristic findings consisted of angiodysplastic lesions with dilated and tortuous feeding arteries and early draining veins ( 10,11 ). Chuang et al ( 10 ) reported angiographic observations in three patients presumed to have HHT and pancreatic AVMs. They described the case of a 56-year-old man with HHT who underwent clinically indicated diagnostic angiography. Arteriographic results showed dilated dorsal and transverse pancreatic arteries with an extensive racemose network in the corporeal and caudal portions of the pancreas. Pathologic examination results demonstrated diffuse AVMs and associated signs of chronic pancreatitis in the corporeal and caudal portions. The second patient was a 7-month-old male infant presenting with hematemesis and melena. Arteriographic results showed multiple AVMs involving the pancreas and the gastrointestinal tract. The patient had no other criteria of HHT but was probably too young to express the criteria needed to diagnose HHT ( 3,12 ). The third patient had no other criteria of HHT, and the AVMs of the pancreas were an isolated finding. In another study conducted in patients with HHT, Lande et al ( 11 ) reported angiographic findings in three patients who presented with chronic gastrointestinal bleeding. Diagnostic angiographic results revealed intestinal telangiectases in all three patients. In one patient, a pancreatic AVM supplied by a small artery and accompanied by an early draining vein was found. Compared with angiography, in which different arterial territories should be evaluated selectively, multidetector CT allows full coverage of the pancreas during a single breath hold after administration of iodinated contrast material. One of the theoretical advantages of angiography is to allow therapeutic procedures such as embolization. However, all patients in our study were asymptomatic, so an invasive examination was not justified except in one case of associated splenic aneurysm. This patient required diagnostic angiography performed at the time of embolization of a large splenic aneurysm diagnosed by using multidetector CT. Whereas multidetector CT results exhibited only one arteriovenous fistula and multiple telangiectases, angiographic results demonstrated multiple arteriovenous fistulas. Therefore, telangiectases and arteriovenous fistulas may be different manifestations of the same pathologic entity as demonstrated in Figure 2. Small fistulas may mimic telangiectases at contrast-enhanced imaging. More recently, two case reports of pancreatic telangiectases diagnosed with the use of contrast-enhanced multidetector CT in patients with HHT were published ( 13,14 ). The pancreatic telangiectases consisted of hypervascular nodules located in the pancreatic parenchyma ( 13,14 ). However, in none of these studies was the prevalence of pancreatic involvement in patients with HHT assessed to any extent. In our series, though our numbers were small, which was a study limitation, pancreatic involvement with pancreatic telangiectases and/or AVMs was found in 31% of patients. This finding suggests that the pancreas should be assessed closely when a subject who is known to have or is suspected of having HHT undergoes multidetector CT. On the basis of our findings, pancreatic telangiectases are highly enhanced round or irregular lesions easily diagnosed during the arterial phase after administration of iodinated contrast material. During the portal phase, pancreatic telangiectases may no longer be visible in all cases. Thus, the arterial phase (35 seconds after intravenous injection of iodinated contrast material in our study) should be favored as the most sensitive phase for detecting pancreatic telangiectases. A differential diagnosis of lesions enhancing during the arterial phase should be included, particularly in patients without a diagnosis of HHT. For example, neuroendocrine pancreatic tumors or hypervascular pancreatic metastases may manifest as enhancing nodules during arterial phase imaging and may mimic telangiectases ( 15,16 ). The diagnostic value of other imaging techniques, such as magnetic resonance imaging or contrast-enhanced US, to assess pancreatic involvement in patients with HHT has not yet been investigated but may represent alternative imaging modalities to assess the pancreas in those with HHT. A limitation of our study was the absence of angiography as the reference standard to assess and confirm all cases of pancreatic involvement by HHT. However, this limitation cannot be overcome, because all of our study population was asymptomatic, so there was no clinical indication for angiography. In the literature, we found only one case in which HHT of the pancreas was implicated as a cause of symptoms in a patient with HHT-induced pancreatitis due to a submucosal angiodysplastic lesion of the ampulla of Vater ( 17 ). According to the Curaçao criteria, a definitive diagnosis of HHT requires that at least three criteria are present. In patients with only two criteria, the diagnosis of HHT is likely but not sure. In the subgroup of patients without visceral involvement, identification of pancreatic telangiectases may provide the third diagnostic criterion as occurred in one patient in our study who had pancreatic telangiectases as the only visceral involvement related to HHT. In conclusion, patients with HHT may develop visceral lesions, including AVMs and telangiectases, particularly in the lung, brain, or liver. In our series, we found pancreatic involvement in 31% of patients with a confirmed diagnosis of HHT, all of whom were asymptomatic. Radiologists should be aware that pancreatic involvement commonly is found in patients with HHT and manifests Radiology: Volume 254: Number 2 February 2010 n radiology.rsna.org 483

6 with pancreatic telangiectases or AVMs that are best seen during arterial phase multidetector CT. Such lesions should be included in the differential diagnosis of hypervascular lesions of the pancreas in these patients. Acknowledgments: We thank participating physicians from the Paris HHT Center, Hôpital Ambroise Paré, Université Paris Ouest: J.H. Blondel, MD, ENT Department, B. Raffestin, MD, Functional Exploration Laboratory, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest. We thank A. Ozanne, MD, Department of Neuroradiology and P. Lasjaunias (in memoriam), Department of Neuroradiology, Centre Hospitalier de Bicêtre, Assistance Publique, Hôpitaux de Paris, Université Paris Sud. References 1. Fuchizaki U, Miyamori H, Kitagawa S, Kaneko S, Kobayashi K. Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). Lancet 2003 ; 362 : Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J 2003 ; 79 : Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler- Weber syndrome). Am J Med Genet 2000 ; 91 : Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995 ; 333 : Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000 ; 343 : Buscarini E, Buscarini L, Danesino C, et al. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family. J Hepatol 1997 ; 26 : Buscarini E, Plauchu H, Garcia Tsao G, et al. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int 2006 ; 26 : Ianora AA, Memeo M, Sabba C, Cirulli A, Rotondo A, Angelelli G. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement. Radiology 2004 ; 230 : Ravard G, Soyer P, Boudiaf M, et al. Hepatic involvement in hereditary hemorrhagic telangiectasia: helical computed tomography features in 24 consecutive patients. J Comput Assist Tomogr 2004 ; 28 : Chuang VP, Pulmano CM, Walter JF, Cho KJ. Angiography of pancreatic arteriovenous malformation. AJR Am J Roentgenol 1977 ; 129 : Lande A, Bedford A, Schechter LS. The spectrum of arteriographic findings in Osler- Weber-Rendu disease. Angiology 1976 ; 27 : Grannis FW, Foulk WT, Miller WE, Payne WS. Diagnosis and management of an arteriovenous fistula of pancreas and duodenum. Mayo Clin Proc 1973 ; 48 : Jaskolka J, Wu L, Chan RP, Faughnan ME. Imaging of hereditary hemorrhagic telangiectasia. AJR Am J Roentgenol 2004 ; 183 : Siddiki H, Doherty MG, Fletcher JG, et al. Abdominal findings in hereditary hemorrhagic telangiectasia: pictorial essay on 2D and 3D findings with isotropic multiphase CT. RadioGraphics 2008 ; 28 : Ghavamian R, Klein KA, Stephens DH, et al. Renal cell carcinoma metastatic to the pancreas: clinical and radiological features. Mayo Clin Proc 2000 ; 75 : Marcos HB, Libutti SK, Alexander HR, et al. Neuroendocrine tumors of the pancreas in von Hippel-Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison. Radiology 2002 ; 225 : Sakai N, Yoshidome H, Ito H, et al. Successful treatment for ampullary submucosal bleeding-induced pancreatitis: a rare sequela of hereditary hemorrhagic telangiectasia. Hepatogastroenterology 2005 ; 52 : radiology.rsna.org n Radiology: Volume 254: Number 2 February 2010