World Journal of - bsdwebstorage.blob.core.windows.net · The World Journal of Radiology Editorial Board consists of 365 members, representing a team of worldwide experts in radiology

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World Journal of RadiologyWorld J Radiol 2015 October 28; 7(10): 306-360

ISSN 1949-8470 (online)

EDITORS-IN-CHIEFKai U Juergens, BremenEdwin JR van Beek, EdinburghThomas J Vogl, Frankfurt

GUEST EDITORIAL BOARD MEMBERSWing P Chan, TaipeiChung-Huei Hsu, Taipei Chin-Chang Huang, TaipeiTsong-Long Hwang, TaoyuanJung-Lung Hsu, TaipeiChia-Hung Kao, TaichungYu-Ting Kuo, Tainan Hon-Man Liu, Taipei Hui-Lung Liang, KaohsiungChun Chung Lui, KaohsiungSen-Wen Teng, Taipei Yung-Liang (William) Wan, Taoyuan

MEMBERS OF THE EDITORIAL BOARD

Afghanistan

Takao Hiraki, Okayama

Argentina

Patricia Carrascosa, Vicente LopezMaria C Ziadi, Rosario

Australia

Lourens Bester, SydneyGemma A Figtree, Sydney

Stuart M Grieve, SydneyWai-Kit Lee, FitzroyPrabhakar Ramachandran, Melbourne

Austria

Herwig R Cerwenka, GrazGudrun M Feuchtner, InnsbruckBenjamin Henninger, InnsbruckRupert Lanzenberger, ViennaShu-Ren Li, ViennaVeronika Schopf, ViennaTobias De Zordo, Innsbruck

Belgium

Steve Majerus, LiegeKathelijne Peremans, Merelbeke

Brazil

Clerio F Azevedo, Rio de JaneiroPatrícia P Alfredo, São PauloEduardo FC Fleury, São PauloEdward Araujo Júnior, São PauloWellington P Martins, Ribeirao PretoRicardo A Mesquita, Belo HorizonteVera MC Salemi, São PauloClaudia Szobot, Porto AlegreLilian YI Yamaga, São Paulo

Canada

Marie Arsalidou, TorontoOtman A Basir, Waterloo

Tarik Zine Belhocine, TorontoJames Chow, TorontoTae K Kim, TorontoAnastasia Oikonomou, Toronto

China

Hong-Wei Chen, WuxiFeng Chen, HangzhouJian-Ping Chu, GuangzhouGuo-Guang Fan, ShenyangBu-Lang Gao, ShijiazhuangQi-Yong Gong, ChengduYing Han, BeijingXian-Li Lv, BeijingYi-Zhuo Li, GuangzhouXiang-Xi Meng, HarbinYun Peng, BeijingJun Shen, GuangzhouZe-Zhou Song, HangzhouWai Kwong Tang, Hong KongGang-Hua Tang, GuangzhouJie Tian, BeijingLu-Hua Wang, BeijingXiao-bing Wang, Xi'anYi-Gen Wu, NanjingKai Wu, GuangzhouHui-Xiong Xu, ShanghaiZuo-Zhang Yang, KunmingXiao-Dan Ye, ShanghaiDavid T Yew, Hong KongTing-He Yu, ChongqingZheng Yuan, ShanghaiMin-Ming Zhang, HangzhouYudong Zhang, NanjingDong Zhang, ChongQingWen-Bin Zeng, Changsha

Editorial Board2014-2017

World Journal of RadiologyW J R

The World Journal of Radiology Editorial Board consists of 365 members, representing a team of worldwide experts in radiology. They are from 36 countries, including Afghanistan (1), Argentina (2), Australia (5), Austria (7), Belgium (2), Brazil (8), Canada (6), Chile (1), China (43), Croatia (1), Denmark (4), Egypt (6), France (5), Germany (22), Greece (10), India (12), Iran (6), Ireland (2), Israel (3), Italy (47), Japan (13), Netherlands (1), New Zealand (1), Pakistan (1), Poland (2), Portugal (1), Serbia (1), Singapore (3), Slovakia (1), South Korea (18), Spain (4), Sweden (2), Switzerland (4), Thailand (1), Turkey (26), United Kingdom (11), and United States (82).

I January 28, 2014WJR|www.wjgnet.com

Yue-Qi Zhu, Shanghai

Croatia

Goran Kusec, Osijek

Denmark

Poul E Andersen, OdenseLars J Petersen, AalborgThomas Z Ramsoy, FrederiksbergMorten Ziebell, Copenhagen

Egypt

Mohamed F Bazeed, MansouraMohamed Abou El-Ghar, MansouraReem HA Mohamed, CairoMohamed R Nouh, AlexandriaAhmed AKA Razek, MansouraAshraf A Zytoon, Shebin El-Koom

France

Sabine F Bensamoun, CompiègneRomaric Loffroy, DijonStephanie Nougaret, MontpellierHassane Oudadesse, RennesVincent Vinh-Hung, Fort-de-France

Germany

Henryk Barthel, LeipzigPeter Bannas, HamburgMartin Beeres, FrankfurtIlja F Ciernik, DessauA Dimitrakopoulou-Strauss, HeidelbergPeter A Fasching, ErlanegnAndreas G Schreyer, RegensburgPhilipp Heusch, DuesseldorfSonja M Kirchhoff, MunichSebastian Ley, MunichAdel Maataoui, Frankfurt am MainStephan M Meckel, FreiburgHans W Muller, DuesseldorfKay Raum, BerlinDirk Rades, LuebeckMarc-Ulrich Regier, HamburgAlexey Surov, HalleMartin Walter, MagdeburgAxel Wetter, EssenChristoph Zilkens, Düsseldorf

Greece

Panagiotis Antoniou, ThessalonikiNikos Efthimiou, AthensDimitris Karnabatidis, PatrasGeorge Latsios, AthensStylianos Megremis, Iraklion

Alexander D Rapidis, AthensKiki Theodorou, LarissaIoannis A Tsalafoutas, AthensEvanthia E Tripoliti, IoanninaAthina C Tsili, Ioannina

India

Ritesh Agarwal, ChandigarhChandan J Das, New DelhiPrathamesh V Joshi, MumbaiNaveen Kalra, ChandigarhChandrasekharan Kesavadas, TrivandrumJyoti Kumar, New DelhiAtin Kumar, New DelhiKaushala P Mishra, AllahabadDaya N Sharma, New DelhiBinit Sureka, New DelhiSanjay Sharma, New DelhiRaja R Yadav, Allahabad

Iran

Majid Assadi, BushehrSeyedReza Najafizadeh, TehranMohammad Ali Oghabian, TehranAmir Reza Radmard, TehranRamin Sadeghi, MashhadHadi Rokni Yazdi, Tehran

Ireland

Tadhg Gleeson, WexfordFrederik JAI Vernimmen, Cork

Israel

Dafna Ben Bashat, Tel AvivAmit Gefen, Tel AvivTamar Sella, Jerusalem

ItalyAdriano Alippi, RomeDante Amelio, TrentoMichele Anzidei, Rome Filippo F Angileri, MessinasStefano Arcangeli, RomeRoberto Azzoni, San Donato milaneseTommaso V Bartolotta, PalermoTommaso Bartalena, ImolaLivia Bernardin, San BonifacioFederico Boschi, VeronaSergio Casciaro, LecceEmanuele Casciani, RomeMusa M Can, NapoliAlberto Cuocolo, NapoliMichele Ferrara, Coppito Mauro Feola, FossanoGiampiero Francica, Castel VolturnoLuigi De Gennaro, RomeGiulio Giovannetti, Pisa

Francesca Iacobellis, NapoliFormato Invernizzi, Monza BrianzaFrancesco Lassandro, NaplesLorenzo Livi, FlorencePier P Mainenti, NapoliLaura Marzetti, ChietiGiuseppe Malinverni, CrescentinoEnrica Milanesi, TurinGiovanni Morana, TrevisoLorenzo Monti, MilanSilvia D Morbelli, GenoaBarbara Palumbo, PerugiaCecilia Parazzini, MilanStefano Pergolizzi, MessinaAntonio Pinto, NaplesCamillo Porcaro, RomeCarlo C Quattrocchi, RomeAlberto Rebonato, PerugiaGiuseppe Rizzo, RomeRoberto De Rosa, NaplesDomenico Rubello, RovigoAndrea Salvati, BariSergio Sartori, FerraraLuca M Sconfienza, MilanoGiovanni Storto, RioneroNicola Sverzellati, ParmaAlberto S Tagliafico, GenovaNicola Troisi, Florence

JapanYasuhiko Hori, ChibaHidetoshi Ikeda, KoriyamaMasahito Kawabori, SapporoTamotsu Kamishima, SapporoHiro Kiyosue, YufuYasunori Minami, Osaka-sayamaYasuhiro Morimoto, KitakyushuSatoru Murata, TokyoShigeki Nagamachi, MiyazakiHiroshi Onishi, YamanashiMorio Sato, Wakayama ShiYoshito Tsushima, MaebashiMasahiro Yanagawa, Suita

Netherlands

Willem Jan van Rooij, Tilburg

New Zealand

W Howell Round, Hamilton

Pakistan

Wazir Muhammad, Abbottabad

Poland

Maciej S Baglaj, Wroclaw

II January 28, 2014WJR|www.wjgnet.com

Piotr Czauderna, Gdansk

Portugal

Joao Manuel RS Tavares, Porto

Serbia

Olivera Ciraj-Bjelac, Belgrade

Singapore

Gopinathan Anil, SingaporeTerence KB Teo, SingaporeCher Heng Tan, Singapore

Slovakia

Stefan Sivak, Martin

South Korea

Ki Seok Choo, BusanSeung Hong Choi, SeoulDae-Seob Choi, Jinju Hong-Seok Jang, SeoulYong Jeong, DaejeonChan Kyo Kim, SeoulSe Hyung Kim, SeoulJoong-Seok Kim, SeoulSang Eun Kim, SeongnamSung Joon Kwon, SeoulJeong Min Lee, SeoulIn Sook Lee, BusanNoh Park, GoyangChang Min Park, SeoulSung Bin Park, SeoulDeuk Jae Sung, SeoulChoongsoo Shin, SeoulKwon-Ha Yoon, Iksan

Spain

Miguel A De Gregorio, ZaragozaAntonio Luna, JaénEnrique Marco de Lucas, SantanderFernando Ruiz Santiago, Granada

Sweden

Dmitry Grishenkov, StockholmTie-Qiang Li, Stockholm

Switzerland

Nicolau Beckmann, BaselChristian Boy, BernGiorgio Treglia, Bellinzona

Stephan Ulmer, Kiel

Thailand

Sirianong Namwongprom, Chiang Mai

Turkey

Kubilay Aydin, IstanbulRamazan Akdemir, SakaryaSerhat Avcu, Ankara Ayse Aralasmak, IstanbulOktay Algin, AnkaraNevbahar Akcar, MeselikBilal Battal, AnkaraZulkif Bozgeyik, ElazigNazan Ciledag, AakaraFuldem Y Donmez, AnkaraGulgun Engin, IstanbulAhmet Y Goktay, IzmirOguzhan G Gumustas, BursaKaan Gunduz, AnkaraPelin Ozcan Kara, MersinKivanc Kamburoglu, AnkaraOzgur Kilickesmez, IstanbulFuruzan Numan, IstanbulCem Onal, AdanaOzgur Oztekin, IzmirSeda Ozbek (Boruban), KonyaSelda Sarikaya, ZonguldakFigen Taser, KutahyaBaran Tokar, EskisehirEnder Uysal, IstanbulEnsar Yekeler, Istanbul

United Kingdom

Indran Davagnanam, LondonM DC Valdés Hernández, EdinburghAlan Jackson, ManchesterSuneil Jain, BelfastLong R Jiao, LondonMiltiadis Krokidis, CambridgePradesh Kumar, LiverpoolPeter D Kuzmich, DerbyGeorgios Plataniotis, BrightonVanessa Sluming, Liverpool

United States

Garima Agrawal, Saint LouisJames R Brasic, BaltimoreRajendra D Badgaiyan, BuffaloUlas Bagci, BethesdaAnat Biegon, Stony Brook Ramon Casanova, Winston SalemWenli Cai, BostonZheng Chang, DurhamCorey J Chakarun, Long BeachKai Chen, Los AngelesHyun-Soon Chong, ChicagoMarco Cura, DallasRavi R Desai, BensalemDelia DeBuc, MiamiCarlo N De Cecco, Charleston

Timm-Michael L Dickfeld, BaltimoreSubba R Digumarthy, BostonHuy M Do, StanfordTodd A Faasse, Grand RapidsSalomao Faintuch, BostonGirish M Fatterpekar, New YorkDhakshinamoorthy Ganeshan, HoustonRobert J Griffin, Little RockAndrew J Gunn, BostonSandeep S Hedgire, BostonTimothy J Hoffman, ColumbiaMai-Lan Ho, San FranciscoJuebin Huang, JacksonAbid Irshad, CharlestonMatilde Inglese, New YorkEl-Sayed H Ibrahim, JacksonvillePaul R Julsrud, RochesterPamela T Johnson, BaltimoreMing-Hung Kao, TempeSunil Krishnan, HoustonRichard A Komoroski, CincinnatiSandi A Kwee, HonoluluKing Kim, Ft. LauderdaleGuozheng Liu, WorcesterYiyan Liu, NewarkVenkatesh Mani, New YorkLian-Sheng Ma, PleasantonRachna Madan, BostonZeyad A Metwalli, HoustonYilong Ma, ManhassetHui Mao, AtlantaFeroze B Mohamed, PhiladelphiaGul Moonis, BostonJohn L Nosher, New BrunswickRahmi Oklu, BostonAytekin Oto, ChicagoBishnuhari Paudyal, PhiladelphiaRajul Pandya, YoungstownChong-Xian Pan, SacramentoJay J Pillai, BaltimoreNeal Prakash, DuarteReza Rahbar, BostonAli S Raja, BostonGustavo J Rodriguez, El PasoDavid J Sahn, Portlsand Steven Schild, ScottsdaleAli R Sepahdari, Los AngelesLi Shen, IndianapolisJP Sheehan, CharlottesvilleAtul B Shinagare, BostonSarabjeet Singh, BostonCharles J Smith, ColumbiaKenji Suzuki, ChicagoMonvadi Srichai-Parsia, WashingtonSree H Tirumani, BostonHebert A Vargas, New YorkSachit Verma, PhiladelphiaYoichi Watanabe, MinneapolisLi Wang, Chapel HillCarol C Wu, BostonShoujun Xu, HoustonMin Yao, ClevelandXiaofeng Yang, AtlantaQingbao Yu, AlbuquerqueAifeng Zhang, ChicagoChao Zhou, BethlehemHongming Zhuang, Philadelphia

III January 28, 2014WJR|www.wjgnet.com

EDITORIAL306 Locoregionaltreatmentforhepatocellularcarcinoma:Thebestisyettocome

Kalra N, Gupta P, Chawla Y, Khandelwal N

REVIEW319 Diffusion-weightedimagingofpancreaticcancer

De Robertis R, Tinazzi Martini P, Demozzi E, Dal Corso F, Bassi C, Pederzoli P, D'Onofrio M

MINIREVIEWS329 Malformationsofcorticaldevelopment:3Tmagneticresonanceimagingfeatures

Battal B, Ince S, Akgun V, Kocaoglu M, Ozcan E, Tasar M

336 Evaluationofprimaryadrenalinsufficiencysecondarytotuberculousadrenalitiswithcomputedtomography

andmagneticresonanceimaging:Currentstatus

Huang YC, Tang YL, Zhang XM, Zeng NL, Li R, Chen TW

343 Functionalassessmentoftransplantedkidneyswithmagneticresonanceimaging

Wang YT, Li YC, Yin LL, Pu H, Chen JY

ORIGINAL ARTICLE

Retrospective Cohort Study

350 Relevantincidentalfindingsatabdominalmulti-detectorcontrast-enhancedcomputedtomography:A

collateralscreening?

Sconfienza LM, Mauri G, Muzzupappa C, Poloni A, Bandirali M, Esseridou A, Tritella S, Secchi F, Di Leo G, Sardanelli F

CASE REPORT357 Delayeddiagnosisofisolatedalarligamentrupture:Acasereport

Kaufmann RA, Marzi I, Vogl TJ


Contents Monthly Volume 7 Number 10 October 28, 2015

� October 28, 2015|Volume 7|�ssue 10|WJR|www.wjgnet.com

Contents

NAMEOFJOURNALWorld Journal of Radiology

ISSNISSN 1949-8470 (online)

LAUNCHDATEDecember 31, 2009

FREQUENCYMonthly

EDITORS-IN-CHIEFKai U Juergens, MD, Associate Professor, MRT und PET/CT, Nuklearmedizin Bremen Mitte, ZE-MODI - Zentrum für morphologische und moleku-lare Diagnostik, Bremen 28177, Germany

Edwin JR van Beek, MD, PhD, Professor, Clinical Research Imaging Centre and Department of Medi-cal Radiology, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Thomas J Vogl, MD, Professor, Reader in Health Technology Assessment, Department of Diagnos-tic and Interventional Radiology, Johann Wolfgang

FLYLEAF

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Xiang Li Responsible Science Editor: Shui QiuResponsible Electronic Editor: Xiao-Kang Jiao Proofing Editorial Office Director: Jin-Lei WangProofing Editor-in-Chief: Lian-Sheng Ma

Goethe University of Frankfurt, Frankfurt 60590, Germany

EDITORIALOFFICEJin-Lei Wang, DirectorXiu-Xia Song, Vice DirectorWorld Journal of RadiologyRoom 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, ChinaTelephone: +86-10-59080039Fax: +86-10-85381893E-mail: [email protected] Desk: http://www.wjgnet.com/esps/helpdesk.aspxhttp://www.wjgnet.com

PUBLISHERBaishideng Publishing Group Inc8226 Regency Drive, Pleasanton, CA 94588, USATelephone: +1-925-223-8242Fax: +1-925-223-8243E-mail: [email protected] Desk: http://www.wjgnet.com/esps/helpdesk.aspxhttp://www.wjgnet.com

PUBLICATIONDATEOctober 28, 2015

COPYRIGHT© 2015 Baishideng Publishing Group Inc. Articles published by this Open-Access journal are distributed under the terms of the Creative Commons Attribu-tion Non-commercial License, which permits use, dis-tribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.

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ABOUT COVER EditorialBoardMemberofWorldJournalofRadiology ,GiulioGiovannetti,PhD,ResearchScientist,InstituteofClinicalPhysiology,NationalResearchCouncil,

56124Pisa,Italy

World Journal of Radiology (World J Radiol, WJR, online ISSN 1949-8470, DOI: 10.4329) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians.

WJR covers topics concerning diagnostic radiology, radiation oncology, radiologic physics, neuroradiology, nuclear radiology, pediatric radiology, vascular/interventional radiology, medical imaging achieved by various modalities and related methods analysis. The current columns of WJR include editorial, frontier, diagnostic advances, therapeutics advances, field of vision, mini-reviews, review, topic highlight, medical ethics, original articles, case report, clinical case conference (clinicopathological conference), and autobi-ography.

We encourage authors to submit their manuscripts to WJR. We will give priority to manuscripts that are supported by major national and international foundations and those that are of great basic and clinical significance.

World Journal of Radiology is now indexed in PubMed Central, PubMed, Digital Object Iden-tifier, and Directory of Open Access Journals.

I-III EditorialBoard

AIM AND SCOPE

��

World Journal of RadiologyVolume 7 Number 10 October 28, 2015

INDEXING/ABSTRACTING

�� October 28, 2015|Volume 7|�ssue 10|WJR|www.wjgnet.com

treatment modalities capable of achieving a cure are hepatic resection and hepatic transplantation. However, most patients are not candidates for these therapies. Overall, treatment options are driven by the stage of HCC. Early-stage disease is treated with ablative therapies, with radiofrequency ablation the ablative therapy of choice. Microwave ablation and irreversible electroporation are the other upcoming alternatives. Intermediate-stage disease is managed with transarterial chemoembolization (TACE), while advanced-stage disease is managed by sorafenib, with TACE and radioembolization as other alternatives.

Key words: Hepatocellular carcinoma; High intensity focussed ultrasound; Irreversible electroporation; Microwave ablation; Radiofrequency ablation

© The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: Treatment of hepatocellular carcinoma is dependent on the stage of disease. Early-stage disease is managed by resection. Radiofrequency ablation (RFA), is becoming an attractive alternative for very early-stage disease. Early-stage disease is treated with ablative therapies. RFA is the ablative therapy of choice. RFA, however, is not effective in all cases. Microwave ablation and irreversible electroporation are upcoming alternatives. Transarterial chemoembolization (TACE) is the modality of choice for intermediate-stage disease. TACE-based multimodal treatment is becoming acceptable. Advanced-stage disease is managed by sorafenib. However, TACE and radioembolization are other alternatives.

Kalra N, Gupta P, Chawla Y, Khandelwal N. Locoregional treatment for hepatocellular carcinoma: The best is yet to come. World J Radiol 2015; 7(10): 306-318 Available from: URL: http://www.wjgnet.com/1949-8470/full/v7/i10/306.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.306

Locoregional treatment for hepatocellular carcinoma: The best is yet to come

Naveen Kalra, Pankaj Gupta, Yogesh Chawla, Niranjan Khandelwal

Naveen Kalra, Pankaj Gupta, Niranjan Khandelwal, Deparment of Radiodiagnosis and Imaging, PGIMER, Chandigarh 160012, India

Yogesh Chawla, Deparment of Hepatology, PGIMER, Chandigarh 160012, India

Author contributions: Kalra N conceived the issues which formed the content of the manuscript; Gupta P wrote the manuscript; Kalra N, Gupta P, Chawla Y and Khandelwal N revised the manuscript.

Conflict-of-interest statement: The authors have no conflict of interests.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Naveen Kalra, MBBS, MD, Professor, Department of Radiodiagnosis and Imaging, PGIMER, Sector 12, Chandigarh 160012, India. [email protected]: +91-172-2756380

Received: April 10, 2015 Peer-review started: April 11, 2015 First decision: June 24, 2015Revised: September 6, 2015 Accepted: October 1, 2015 Article in press: October 8, 2015Published online: October 28, 2015

AbstractHepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide. The only definitive

EDITORIAL

306 October 28, 2015|Volume 7|Issue 10|WJR|www.wjgnet.com


Submit a Manuscript: http://www.wjgnet.com/esps/Help Desk: http://www.wjgnet.com/esps/helpdesk.aspxDOI: 10.4329/wjr.v7.i10.306

World J Radiol 2015 October 28; 7(10): 306-318ISSN 1949-8470 (online)

© 2015 Baishideng Publishing Group Inc. All rights reserved.

INTRODUCTIONHepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and the third-leading cause of cancer-related death[1]. The Barcelona Clinic Liver Cancer (BCLC) classification not only stages but also guides the clinical management of patients with HCC (Table 1 and Figure 1)[2]. An integral component of the BCLC staging is the Child-Pugh classification (Table 2)[3].

The only definitive treatment modalities capable of achieving a cure are hepatic resection and hepatic transplantation. However, a limited number of patients (10% to 20%) are considered fit for these treatments. A large percentage of the remaining patients are managed by so-called liver-directed regional therapies. Among these, methods of tumor ablation (TA) have shown the most clinical promise. In addition to down-staging patients, TA may have a potential curative role, especially in very-early- and early-stage HCCs[4]. The various options for ablative therapies are listed in Table 3.

There has been a significant evolution of TA therapies as an alternative option for patients with unresectable tumors. This has been rendered feasible by significant technical advancements and evidence from well-conducted studies that have suggested improved outcomes in patients treated with TA[5-7].

We will discuss the various treatment options for HCC based on the BCLC staging.

VERY-EARLY-STAGE HCCThe standard treatment in this group is surgical rese-ction. Such patients are unlikely to decompensate after resection and have an excellent 5-year survival rate (> 75%)[8]. The most commonly used surgical technique for this group is anatomic resection, which involves en-bloc removal of a liver segment (supplied by a major portal vein branch and the hepatic artery). This technique is preferred because it theoretically allows the eradication of intrahepatic metastases of HCC. However, a major consideration is treatment-related mortality, which is in the range of 1%-3%[9]. TA methods provide an alternative treatment option for nodules smaller than 2 cm in diameter. Percutaneous radiofre-quency ablation (RFA) is the standard TA technique at most centers worldwide. Lesions that are not sub-capsular, perivascular, or peribiliary are ideal targets for percutaneous RF ablation. In centrally located tumors, RFA perhaps presents a challenge to the dominant position of surgical resection for treatment. A very high complete response rate (97%) and a 5-year survival rate of 68% has been reported with RFA in very-early-stage HCC[10]. Cho et al[11], in their recent decision-analysis study, concluded that RFA and hepatic resection should be considered equally effective for the treatment of very-early HCC. Takayama et al[12] performed a retrospective analysis of 2550 patients (RFA/resection = 1315/1235) with very early HCC, finding no statistically

significant difference in overall survival (OS) rates in the RFA versus resection groups (95% vs 94%). In a recent meta-analysis, there was no significant difference in the overall 1- and 3-year survival and disease-free survival rates between the resection and RFA groups for tumors < 2 cm in diameter[13].

Based on these published data, it is recommended that RFA be considered a first-line treatment option for very-early-stage HCC, with surgical resection reserved for patients for whom individual variables preclude RFA. In certain patients who are not candidates for RFA (e.g., sub-optimal location) or surgery (e.g., increased bilirubin level or signs of portal hypertension), percutaneous ethanol injection (PEI) may be considered[14]. In a randomized trial by Giorgio et al[15], patients with a single HCC ≤ 3 cm were randomly assigned to receive PEI or RFA, and comparable 3-year (74% and 78%, respectively, for each treatment) and 5-year (68% for both treatments) survival rates were found.

EARLY-STAGE HCCResection, liver transplantation, and percutaneous TA are the various treatment options for this large, hetero-geneous group. Besides the percutaneous approach for ablation, other approaches for ablation have been described, including a laparoscopic route and an open surgical route. Advanced techniques are also described for lesions abutting the diaphragm and gastrointestinal tract. The surgical routes for ablation allow treatment of larger lesions, avoiding the hindrances posed by the tissues overlying the liver.

Among the different TA techniques, RFA is currently the favored treatment option for patients with early-stage HCC (Figure 2)[16]. Percutaneous chemical ablation is cost-effective, easy-to-perform, and has found worldwide acceptance for small lesions. Between PEI and percutaneous acetic-acid injection (PAI), multiple studies have failed to show any superiority of one over the other[17]. PEI and PAI are limited by the need for multiple sessions to achieve the clinically desired results. With the introduction of RFA, chemical ablation has decreased in popularity.

There are four types of RF electrodes commercially available: Two models of retractable-needle electrodes (model 70 and model 90 Star-burst XL needles, RITA Medical Systems, Mountain View, CA; LeVeen needle electrode, Boston Scientific, Boston, MA), an internally cooled electrode (Cool-Tip RF electrode; Radionics, Burlington, MA), and a separable clustered electrode (Octopus®; STARmed, Goyang, Korea)[6].

The RITA RF electrode consists of a 14-gauge, insulated outer needle that has nine retractable, curved electrodes of various lengths. When deployed, the device assumes the approximate configuration of a Christmas tree. The LeVeen RF electrode has retractable, curved electrodes and an insulated, 17-gauge outer needle that contains 10 solid, retractable, curved electrodes. It assumes the configuration of an umbrella upon

Kalra N et al . Locoregional treatment of HCC

307WJR|www.wjgnet.com October 28, 2015|Volume 7|Issue 10|

deployment. The Cool-Tip RF device has an insulated, hollow, 17-gauge needle with an exposed needle tip of variable length. The needle shaft has two internal channels for perfusion with chilled water. In an attempt to increase the size of the possible ablation area, the

manufacturer has placed three of the cooled needles in a parallel, triangular cluster with a common hub (a multi-tined electrode). In the Octopus®, RF energy is applied to two electrodes, while, simultaneously, RF energy is switched between a pair of electrodes. This can create a large ablative zone with a spherical shape that has better efficiency of RF energy delivery over a given treatment time.

In order to achieve therapeutic results similar to those achieved with traditional surgery, surgical margins of approximately 1 cm are required for successful resection by RFA. However, current RFA technology, with internally cooled or expandable electrodes, achieve


BCLC classification

Stage Description Very early PS 0, Child-Pugh A, single HCC, 2 cmEarly PS 0, Child-Pugh A–B, single HCC or 3 nodules, 3 cmIntermediate PS 0, Child-Pugh A–B, multinodular HCCAdvanced PS 1–2, Child-Pugh A–B, portal neoplastic invasion,

nodal metastases, distant metastasesTerminal PS 2, Child-Pugh C

Table 1 Barcelona Clinic Liver Cancer classification[2]

HCC: Hepatocellular carcinoma; BCLC: Barcelona clinic liver cancer.

Child-pugh classification

Finding 1 point 2 points 3 pointsEncephalopathy grade None Mild Severe Ascites Absent Mild to moderate Severe, refractorySerum bilirubin (mg/dL) 2 2-3 > 3Serum albumin (g/dL) > 3.5 2.8-3.5 < 2.8INR < 1.7 1.7-2.2 > 2.2

Table 2 Child-Pugh classification[3]

A: 5–6 points; B: 7–9 points; C: 10–15 points. INR: International normalized ratio.

Chemical ablation PAIPEI

Cryoablation Nitrous oxideLiquid nitrogenArgon

Thermal ablation RFALITTHIFUMWA

Electroporation IRE

Table 3 Various ablative methods for hepatocellular carcinoma

PAI: Percutaneous acetic acid injection; PEI: Percutaneous ethanol injection; RFA: Radiofrequency ablation; LITT: Laser-induced thermotherapy; HIFU: High-intensity focused ultrasound; MWA: Microwave ablation; IRE: Irreversible electroporation.


Figure 1 Flow chart of Barcelona Clinic Liver Cancer based management guidelines for hepatocellular carcinoma[2]. HCC: Hepatocellular carcinoma; RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization.

HCC

Stage 0 PS 0, Child-Pugh A

Stage A-CPS 0-2, Child-Pugh A-B

Stage DPS > 2, Child-Pugh C

Intermediate stage (B)Multinodular, PS 0

Terminal stage (D)

Single 3 nodules ≤ 3 cm

Portal pressure/bilirubin

Normal

Increased Associated diseases

No Yes

Resection Liver transplantation RFA TACE Sorafenib Symptomatic treatment

Curative treatments Palliative treatments

Advanced stage (C)PV invasion, N1, M1, PS 1-2

Early stage (A)Single or 3 nodules

< 3 cm, PS 0

Very early stage (0)Single < 2 cm

RFA is more effective than PEI in terms of better local disease control[14,18-21]. However, in trials by Lencioni et al[14] and Brunello et al[21], the differences in overall 1- and 3-year survival rates between RFA and PEI were not statistically significant. Further, independent meta-analyses of early-stage HCC cases have confirmed the survival benefit conferred by RFA over PEI[22-25].

Recent studies regarding the long-term outcomes of RFA-treated patients have shown consistently high 5-year survival rates in early-stage HCC[26-29]. In studies by Lencioni et al[26] (n = 144), Tateishi et al[27] (n = 221), Choi et al[28] (n = 359), and N’Kontchou et al[29] (n = 67), 3- and 5-year survival rates were reported, respectively, as 76% and 51%, 83% and 63%, 78% and 64%, and 82% and 76% for Child A or BCLC resectable disease[26-29]. In a study by Kalra et al[30], 31 patients with 41 unresectable HCCs were treated with RFA. Over a follow-up period ranging from 3 mo to 6 years, ablation was successful at a rate of 80.5%. Eight patients had tumor recurrences. The survival rate at 1 year in patients who had completed at least 1 year of follow-up was 63.3%[20].

Thus, a question arises: Can RFA replace surgical resection as a first-line treatment for early-stage HCC? Several retrospective studies and a single RCT found no statistically significant difference in survival rates between surgical resection and RFA[31-37].

Chen et al[38] conducted an RCT on 180 patients with a solitary HCC ≤ 5 cm who received either percutaneous RFA or surgical resection. No significant difference was noted in the overall and disease-free survival rates between the RFA and resection groups in terms of their respective 1-year (95.8% and 93.3%) and 4-year (67.9% and 64.0%) OS rates. However, in the RCT by Huang et al[39], the 1-, 3-, and 5-year OS and recurrence-free survival rates in the surgical resection group were significantly higher than in the RFA group (P = 0.001, P = 0.017).

An important factor limiting the success of RFA is tumor size, as RFA may fail to ablate the entire tumor volume for tumors larger than 3 cm along the longest axis, particularly at their periphery. The results of RFA are also greatly affected by tumor location. The presence of a large vessel (3 mm or more) in the

a limited volume of coagulation necrosis, resulting in marginal recurrence rates up to 41%, especially with tumors greater than 3 cm in diameter. Several types of electrodes have been developed to overcome this limitation and achieve larger ablation zones, including perfused, clustered, saline-infused expandable, and multipolar electrodes. In addition, a multiple electrode-switching system can achieve substantially larger ablation volumes than techniques using conventional RF ablation with single electrodes having overlapping ablations[6].

Five randomized, controlled trials (RCTs) have compared RFA and PEI for the treatment of early-stage HCC. The results of three RCTs (Table 4) showed that


Study and treatment Initial complete Treatment Overall survival rate (%) P value

response rate (%) failure rate (%) 1-yr 3-yrLin et al[18]

RFA (n = 52) 96 17 82 74 0.014 PEI (n = 52) 88 45 61 50Shiina et al[19]

RFA (n = 18) 100 2 90 80 0.02 PEI (n = 114) 100 11 82 63Lin et al[20]

RFA (n = 62) 97 16 88 74 0.031 PEI (n = 62) 89 42 96 51

Table 4 Comparison of radiofrequency ablation and percutaneous ethanol injection

PEI: Percutaneous ethanol injection; RFA: Radiofrequency ablation.

A

B

Figure 2 Axial computed tomography images before and after radiofrequency ablation shows an arterial enhancing lesion (arrow, A). That is replaced by a hypodense area without any enhancement following radiofrequency ablation (arrow, B).


vicinity of the lesion reduces heat deposition by a “heat sink” effect[40]. Furthermore, lesions in the vicinity of vital structures like the gallbladder, bile ducts, or colon are difficult to treat due to the inherent risk of thermal damage.

Therefore, when RFA is not precluded by tumor location, it is proposed that solitary HCCs larger than 3 cm and smaller than 5 cm in size should be considered for combination therapy with RFA[41-45]. One of the forms of combination therapy is TACE-preceded RFA. The rationale behind lipiodol TACE-preceded RFA is as follows: a state of transient liver infarction is induced by the lipiodol, which regurgitates into the portal branches via the peribiliary venous plexus, thereby decreasing the heat sink effect, expanding the ablative area, and promoting the ablation of satellite lesions[46]. Several studies have reported significantly better survival rates with TACE-preceded RFA compared to RFA alone for intermediate-sized lesions[45,47-48]. In another administration method, TACE may follow RFA, with TACE expected to handle the peripheral part of a tumor where RFA achieves sub-optimal temperatures[45]. A phase Ⅲ randomized, double-blinded, placebo-controlled study investigating the efficacy and safety of thermally sensitive liposomal doxorubicin in combination with RFA compared to RFA alone in the treatment of unresectable HCC is ongoing[49].

When RFA cannot be performed, largely in view of tumor location, TACE combined with drug eluting beads (DEB) is an alternative. Complete necrosis was reported in 77% patients undergoing DEB-TACE prior to transplantation[50].

HCCs larger than 5 cm comprise another critical group in early-stage HCC. These patients are precluded from transplantation, according to the Milan guidelines, yet surgical resection should be considered for these patients as ablative therapies are unlikely to be effective with lesions of this size[51]. Combination therapies are also expected to be inferior to surgical resection.

Other thermal ablative therapies-including laser-induced thermotherapy (LITT), high-intensity focused ultrasound (HIFU), and microwave ablation (MWA) and irreversible electroporation (IRE) are other alternative modes of therapy; however, these are still evolving technologies and there is too little data at present to put forth concrete recommendations. Of the above-mentioned alternatives, MWA and IRE appear promising and may even supplant RFA in the future.

LITT is based on the use of an Nd-YAG (neodymium: yttrium aluminum garnet) diode laser that allows the delivery of a precise amount of energy to a pre-defined region. Maximal tissue penetration and the desired therapeutic results are achieved by producing slow heating within its therapeutic window. Most studies with LITT have been reported in patients with liver metastases, with favorable survival rates and an acceptable complication profile[52,53]. A single trial of LITT for HCC evaluated the efficacy of a combination of TACE and LITT compared to TACE alone. TACE and LITT

were performed in 54 patients, while TACE alone was administered to 51 patients. After a follow-up of 24 mo, survival rates were significantly better in the TACE and LITT (79.6%) than in the TACE alone (60.8%) group[54]. A multicenter study (involving 432 cirrhotic patients with a single tumor ≤ 4 cm or three or fewer nodules ≤ 3 cm each, comprising together 548 lesions), reported that the ideal candidates for laser ablation are younger (< 73 years) with normal serum albumin levels. Child-Pugh class A patients with tumor size ≤ 3 cm and a well-differentiated histologic pattern who achieved an initially complete ablation had median survival of 65 mo. Median time to recurrence was 24 mo, and median disease-free survival was 26 mo[55]. However, this form of treatment is not preferred, largely due to the availa-bility of better alternative ablative therapies.

In HIFU, high-intensity ultrasound in the range of 100-10000 W/cm2 is delivered to a focal region. The absorption and subsequent intense acoustic energy generates temperatures above 60 ℃ in a short span of time, producing coagulative necrosis. Successful ablation of HCC has been reported by several stu-dies[56-58]. In a recent study, Ng et al[59] presented data on 49 patients treated with HIFU for unresectable HCC. Complete clinical response in this series was 79.5%, and 1- and 3-year survival rates were 87.7% and 62.4%, respectively. In another series by Xu et al[55], 145 patients with HCC were treated with HIFU. Symptom improvement and pain relief was achieved in 84.8% of patients[56]. A two-year survival rate of 80% was reported for early-stage disease. Chan et al[57] compared HIFU to RFA in 103 patients with HCC. HIFU was associated with higher complication rates (skin burns and pleural effusion) than was RFA. There was no significant difference in the 3-year OS rate between HIFU and RFA[57]. A completely extracorporeal HIFU device for treatment of HCC, though clinically feasible, is capable of ablating only small-volume lesions unless a partial rib resection is performed. Moreover, this procedure is associated with attenuation and various complications, including skin burns and gastric lesions. For these reasons, an open procedure seems appropriate despite being more invasive. Besides allowing a better staging of malignancies, large areas of liver can be rapidly ablated in an open procedure. In a feasibility study by Dupré et al[60], this approach was found to be effective in patients with colorectal liver metastases. In 30 ablations performed in 15 patients, intra-operative HIFU was found to be safe, feasible, and without damage to neighboring tissues[60]. Recently, Gandini evaluated in an animal model the use of HIFU for assisting liver resection in an open procedure[61]. They found that HIFU-assisted liver resection is associated with reduced bleeding risk.

The basic principle of ablation in MWA is heat generation using dielectric hysteresis. High-frequency microwaves (typically 900 to 2500 MHz) lead to polarization and rapid oscillation of the intracellular water molecules. The resulting kinetic energy transfer



produces heat, coagulation necrosis, and TA. The advantages of MWA over RFA are tabulated in Table 5. Shibata et al[62] compared the effectiveness of MWA with that of RFA. There was no statistically significant difference in the effectiveness of the two procedures. However, a trend favoring RFA was recognized in that study with respect to local recurrence and complication rates[62]. In another study by Yin et al[63] comparing the therapeutic efficacy of RFA and MWA in treating HCCs > 3 cm, both RFA and MWA were found to be effective and safe. Several studies have evaluated the efficacy of MWA when used alone in treating HCCs[63]. Sato et al[64], in one of the earliest studies, demonstrated the safety and efficacy of MWA in 19 patients with unresectable HCCs. MWA was potentially curative in 73.7% of patients[64]. The authors concluded that MWA is a safe and potentially curative treatment option in patients with HCCs having advanced liver cirrhosis and multifocal or central tumors. In another case series, 60 patients with initial HCC (n = 15) and recurrent HCC (n

= 45) were treated with MWA. Three-year recurrence free survival rates for initial HCC and recurrent HCC were 36.7% and 8.8%, respectively; 5-year OS for all patients was 43.1%[65]. Several other case series also reported a favorable outcome with MWA[66-68]. A recent study evaluated the efficacy and safety of percutaneous MWA versus TACE for large HCC (5-7 cm). Sixty-four patients were divided into two groups and treated with either MWA or TACE. A higher rate of complete ablation (75%) was achieved with fewer sessions of MWA than of TACE, and MWA displayed a lower incidence of tumor recurrence, de novo lesions, or post-treatment ascites[69].

Though several initial studies have shown favorable results with cryoablation, many recent studies have raised concerns regarding serious side effects and complications associated with this technology, including cryoshock, hypothermia, cracking of the ice ball, hemorr-hage, biloma, abscess, pleural effusion, and death[70,71].

IRE is a non-thermal ablative technique that achi-eves cell death by creating pores in the lipid bilayer of cell membranes using an electric current. This is accomplished by micro- to millisecond electrical pulses (at 1000–3000 V) delivered via needle electrodes, causing loss of cellular homeostasis and eventually cell death (Figures 3 and 4). In contrast to thermal ablative methods that cause coagulative necrosis by gross heat damage to a cell, IRE acts at the level of cellular membranes and produces cell death by apoptosis[72]. As a result, it spares important structures like blood vessels, bile ducts, and tissue stroma[73]. The NanoKnife (AngioDynamics, New York) is the most commonly used commercial device. It utilizes a 2500 V generator system. Advantages of IRE over other ablative techniques are listed in Table 6. A comparison of various ablative techniques in terms of ease of ablation titration, cost, and tissue specificity is given in Table 7.

Early clinical experience with IRE regarding safety and efficacy during ablation of HCC is encouraging. However, most of the available data are short-term. In one of the initial reviews, by Charpentier, IRE was not only found to be safe but also potentially superior to other techniques for lesions abutting major vascular


Achieves higher temperatures and relatively larger ablative zones in a shorter time Ablative zones are more consistent and uniform in characterBetter safety profile Less post procedural pain Not affected by the heat sink effectMultiple applicators can be used simultaneously

Table 5 Advantages of microwave ablation over radiofrequency ablation

A

B

Figure 3 Irreversible electroporation for an early stage hepatocellular carcinoma in left lobe (arrow) (A and B).


Figure 4 Computed tomography 1 mo after irreversible electroporation in the same patient as Figure 4. No residual enhancement is seen (arrow).

structures[73]. In another retrospective review, IRE-specific treatment outcomes, rates of recurrence, and complications were evaluated in 28 patients with tumor locations precluding other forms of ablation. IRE was found to be safe, with only 3% of patients suffering complications. At 6-mo follow-up, recurrence was reported in 3 patients (5.7%)[74]. Several prospective studies have also established the safety and efficacy of IRE. Cannon et al[75] reported a 100% initial success rate with IRE in 44 patients with HCC. Adverse events were noted in 11% of patients; however, all complications resolved within 30 d. Local recurrence-free survival rates of 97.4% and 59.5% were recorded at 3 and 12 mo, respectively. A multi-institutional study evaluated the learning curve associated with IRE. Over 2 years, 150 consecutive patients participated at seven institutions[76]. The authors found that treatments of larger lesions and lesions with a greater degree of vascular involvement could be performed safely and

effectively with increased experience over a period of time. In a recent study, Narayanan et al[77] compared post-procedural pain and tolerance in patients treated with IRE to that related to RFA. A total of 43 patients (RFA 22, IRE 21) were included, and post-procedural pain was comparable in both groups[77]. In another recent trial, Niessen et al[78] evaluated the risk factors associated with short-term local recurrence after IRE. Twenty-five patients with 48 malignant liver lesions (HCC = 22; cholangiocarcinoma = 6; metastases = 20) underwent IRE. Fourteen of the 48 treated lesions (29.2%) showed early local recurrence after 6 mo. Factors predicting short-term local recurrence were tumor volume (> 5 cm3) and underlying disease type (HCC had a significantly favorable outcome compared to metastases and cholangiocarcinoma). However, distances to the surrounding vessels and bile ducts were not significantly associated with local recurrence.

Due to limited data regarding long-term safety and efficacy, the use of IRE on a widespread scale is not recommended at present. The best use of this technology, in the meantime, is for selected patients in whom other currently available ablative treatments are not feasible.

INTERMEDIATE STAGE HCCTACE is recommended as the standard of care for intermediate-stage HCC (Figure 5), based on improved survival demonstrated in a meta-analysis that compared TACE to the best available supportive care or to other, suboptimal therapies[79]. A limitation of this study was the considerable heterogeneity between the individual study designs as well as the study results. Only 2[80,81] of the 6 included RCTs reported a 2-year survival benefit over conservative management[80-85]. Additionally, a recently concluded Cochrane trial concluded that there is no firm evidence to support or refute either TACE or bland transarterial embolization (TAE) for patients with unresectable HCC. The group suggested that more adequately powered and bias-protected trials are needed[86].

Greater standardization of TACE protocols is needed.


Selective cellular target Cell death via apoptosisSparing effect on important structuresNot affected by heat sink (compared to RFA)Sharp boundary between the treated and untreated areas

Table 6 Advantages of irreversible electroporation over other thermal ablative techniques

RFA: Radiofrequency ablation.

RFA MWA IRE

Principle Thermal Thermal Non-thermalCollateral damage + + -Ease of ablation titration + + ++Cost + + ++Duration of therapy + + ++Tissue effect Tumor + + + Nerve + + - Vessels + + - Hepatic architecture + + -

Table 7 Comparison of energy based therapies

RFA: Radiofrequency ablation; MWA: Microwave ablation; IRE: Irreversible electroporation.


B

A

Figure 5 Trans-arterial chemoembolisation of a large hepatocellular carcinoma in right lobe of liver (arrow, A). Following transarterial chemoembolization, there is uniform distribution of lipiodol the lesion (arrow, B).

The basic principle guiding an ideal TACE protocol is to achieve a maximum and sustained concentration of the chemotherapeutic agent in the tumor bed. Systemic exposure, if necessary at all, should be minimized. In an attempt to achieve these goals, embolic microspheres (drug-eluting beads, or DEB) were introduced that are capable of sequestering doxorubicin hydro-chloride from solution through controlled release following sel-ective administration. Compared with lipiodol-based regimens, these increase local drug concentration and, in turn, the efficacy[87]. The PRECISION V trial provides evidence for the efficacy and safety of TACE with DEB compared to conventional TACE[88]. The results from this trial demonstrated greater tolerance, with significant reductions in doxorubicin-related side effects and serious hepatotoxicity compared to conventional TACE. The objective response rate in the TACE with DEB group was significantly better than in the conventional TACE group[88]. An important observation from the trial was that high-dose doxorubicin treatment was successfully achieved in the whole DEB group.

A recent study compared the treatment of HCC with TACE using gelatin sponges or microspheres plus lipiodol-doxorubicin versus doxorubicin-loaded DEB[89]. A total of 158 patients were enrolled in this study. TACE with lipiodol-doxorubicin and gelatin sponges (group A), TACE with lipiodol-doxorubicin and microspheres (group B), and TACE with doxorubicin-loaded DEB (group C) were performed in 64, 41, and 53 patients, respectively. In group C, a significantly higher doxorubicin dosage was achieved and complete response rates were significantly higher[85].

Studies have investigated the ideal size of the microspheres for drug delivery in DEB-TACE. A recent study compared the safety and efficacy of 70-150 μm DEB to 100-300 μm DEBs[90]. A cohort of HCC patients who underwent TACE with two vials of 100-300 μm DEBs was compared to those treated with one vial of 70-150 μm DEBs followed by one vial of 100-300 μm DEBs. Though the short-term efficacy did not differ, TACE with smaller DEBs (70-150 μm) followed by larger DEBs (100-300 μm) was found to be more likely to cause hepatobiliary adverse events.

It remains to be thoroughly evaluated whether the addition of the chemotherapeutic agent to embolic micr-ospheres improves treatment effectiveness. This issue has been addressed in a few studies. In one RCT, bland embolization was compared to embolization with beads loaded with doxorubicin[91]. The results demonstrated a significantly lower tumor-progression rate at 12 mo in the DEB group than in the bland embolization group[91]. Another study established the superiority of DEB-TACE compared to bland embolization[50]. The authors studied the degree of necrosis in explanted livers following TACE with epirubicin-loaded DEB and after bland embolization in patients on a transplant waiting list. Complete necrosis was achieved in 77% of tumors in the DEB group and only 27% of tumors in the bland embolization group, a statistically significant difference

between the two groups[50]. A recent trend has been towards combination

therapy in an attempt to achieve better tumor-free survival rates. Published research supports the advan-tage of various forms of combination therapies with TACE (with lipiodol or DEB). Ginsburg et al[92] compared retrospectively the outcomes and complications of transcatheter arterial chemoembolization using drug-eluting embolic agents combined with RFA or microwave MWA in the treatment of HCCs[92]. A total of 89 patients with HCCs were recruited for combination therapy, with TACE plus RFA (group A) administered to 38 patients and TACE plus MWA (group B) administered to 51 patients. Complete local-tumor response rates were 80.4% and 76.6% for groups A and B, respectively, with no statistically significant difference between the two groups. The median tumor PFS and overall PFS were also comparable between the two groups. The authors concluded that both combination therapies are effective treatments for HCC. Iezzi et al[93], in a recent prospective trial, evaluated the efficacy of single-step RFA and DEB-TACE in patients with single HCCs > 3 cm. The group treated with combined therapy showed significantly lower 2-year recurrence and significantly higher survival rates than did the group treated with chemoembolization alone. In the on-going SPACE trial (Sorafenib or placebo in combination with TACE for intermediate-stage HCC), the potential synergy between TACE (with DEB) and sorafenib is being investigated[94]. The basis for this trial is that hypoxia can lead to neoangiogenesis (a potential situation with TACE monotherapy). An anti-angiogenic agent might inhibit the post-TACE surge in VEGF-mediated signaling, preventing tumor growth. Moreover, systemic administration may suppress tumor foci distant from the TACE site. In phase Ⅱ of the SPACE trial, 307 patients undergoing TACE were randomized to sorafenib (n = 154) or placebo (n = 153) groups. The results from phase Ⅱ reported a hazard ratio (HR) for time-to-tumor progression (TTP) of 0.797 (95%CI: 0.588-1.080; P = 0.072), with median TTP (50th percentile) of 169 and 166 d in the sorafenib and placebo groups, respectively. The primary goal of improving TTP by using sorafenib-TACE with DEB was achieved in the SPACE study. The data from on-going phase Ⅲ trials are awaited to confirm these favorable results.

Studies have also compared the survival of patients following TACE with the survival of patients following the resection of large HCCs. A recent meta-analysis (comprising 12 studies) reported a survival benefit of resection compared to TACE in patients with BCLC stage A and B HCC.

Radioembolization is another therapeutic option for intermediate-stage HCC. The most commonly employed radioembolization technique at present employs microspheres coated with a β-emitting isotope, yttrium 90 (90Y). Similar to TACE, intra-arterially injected microspheres are preferentially delivered to the HCC, with selective emission of high-energy, low-



penetration radiation to the tumor. Several phase Ⅰ and Ⅱ clinical trials have documented the safety of radi-oembolisation[95-98]. The efficacy of radioembolization for the treatment of HCC has also been reported by a number of cohort studies and retrospective analyses. Retrospective studies report that patients with in-termediate-stage HCCs may have similar survival following treatment with either conventional TACE or radioembolization. However, longer time-to-progression and decreased toxicity have been reported in patients receiving radioembolization[99].

ADVANCED-STAGE HCCAccording to the BCLC guidelines, systemic therapy with the multikinase inhibitor sorafenib is considered the standard choice for patients with advanced HCC[100].

Conventionally, TACE is contraindicated in advanced HCC patients who have portal-vein invasion, owing to the risk of hepatic insufficiency[100]. However, recent studies suggest that TACE can be safely performed even in this group[101-103]. Survival benefits in patients with advanced HCC have been suggested by various studies. Song et al[104] reported on the efficacy and safety of TACE-based multimodal treatment in patients with large HCCs (> 10 cm). Of the 146 consecutive patients recruited in the study, 119 patients with portal-vein thrombosis received TACE-based multi-modal treatments (including systemic chemotherapy = 46, radiotherapy = 25, RFA or PEI = 21, surgical resection = 13, and liver transplantation = 4). The remaining 27 received conservative management, comprising the control group. Objective tumor response and OS were significantly better in the TACE-based multimodal treatment groups. Kim et al[105] compared the efficacy of TACE with and without radiotherapy (RT) vs sorafenib for advanced HCC with portal vein tumor thrombosis (PVTT). Of the 557 patients with HCC with PVTT, 295 received TACE, 196 received TACE with RT, and 66 received sorafenib. The TACE plus RT group showed significantly better OS than did either the TACE-alone or the sorafenib groups.

Studies suggest that radioembolization might be an effective treatment option for patients with advanced HCCs. In a recent study by Salem et al[106], a cohort of 291 patients with HCC was treated with 90Y. Of all patients, 52% were BCLC class C. TTP for the entire cohort was 7.9 mo. Sub-group analyses revealed that TTP in the absence of portal vein thrombosis was 15.5 mo while TTP in the presence of portal vein thrombosis was 5.6 mo, suggesting that treatment with 90Y glass microspheres could represent an effective option, especially in patients with portal vein thrombosis for whom TACE is conventionally not thought suitable. Several other studies have also reported favorable results in advanced HCC[107-109]. However, major bodies worldwide have recommended further RCTs to evaluate the safety and efficacy of 90Y[110].

Though there are several emerging techniques for

managing HCCs in different stages of disease, clarity regarding the application and safety of one method over another and about the use of combinations of different methods remains contentious. Well-planned RCTs covering all stages of HCCs are required before a standard of care can be adopted.

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P- Reviewer: Asirvatham SJ, Baiocchi GL, Francica G S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK



Diffusion-weighted imaging of pancreatic cancer

Riccardo De Robertis, Paolo Tinazzi Martini, Emanuele Demozzi, Flavia Dal Corso, Claudio Bassi, Paolo Pederzoli, Mirko D’Onofrio

Riccardo De Robertis, Paolo Tinazzi Martini, Department of Radiology, Casa di Cura Pederzoli, 37019 Peschiera del Garda, Italy

Emanuele Demozzi, Flavia Dal Corso, Mirko D'Onofrio, Verona Comprehensive Cancer Network, Department of Radiology, G.B. Rossi Hospital - University of Verona, 37134 Verona, Italy

Claudio Bassi, Verona Comprehensive Cancer Network - Department of Pancreatic Surgery, G.B. Rossi Hospital - University of Verona, 37134 Verona, Italy

Paolo Pederzoli, Department of Pancreatic Surgery, Casa di Cura Pederzoli, 37019 Peschiera del Garda, Italy

Author contributions: All authors contributed equally to this work; Tinazzi Martini P, Bassi C, Pederzoli P and D’Onofrio M designed the research; Demozzi E and Dal Corso F performed the research and analyzed the data; De Robertis R, Demozzi E and Dal Corso F wrote the paper.

Informed consent statement: The authors declare no potential conflicts of interest for this paper.


Correspondence to: Riccardo De Robertis, MD, Department of Radiology, Casa di Cura Pederzoli, via Monte Baldo 24, 37019 Peschiera del Garda, Italy. [email protected]: +39-45-8124301Fax: +39-45-8027490

Received: January 28, 2015Peer-review started: January 28, 2015First decision: April 14, 2015Revised: April 27, 2015Accepted: August 25, 2015

Article in press: August 28, 2015Published online: October 28, 2015

AbstractMagnetic resonance imaging (MRI) is a reliable and accurate imaging method for the evaluation of patients with pancreatic ductal adenocarcinoma (PDAC). Diffusion-weighted imaging (DWI) is a relatively recent technological improvement that expanded MRI capabilities, having brought functional aspects into conventional morphologic MRI evaluation. DWI can depict the random diffusion of water molecules within tissues (the so-called Brownian motions). Modifications of water diffusion induced by different factors acting on the extracellular and intracellular spaces, as increased cell density, edema, fibrosis, or altered functionality of cell membranes, can be detected using this MR sequence. The intravoxel incoherent motion (IVIM) model is an advanced DWI technique that consent a separate quantitative evaluation of all the microscopic random motions that contribute to DWI, which are essentially represented by molecular diffusion and blood microcirculation (perfusion). Technological imp-rovements have made possible the routine use of DWI during abdominal MRI study. Several authors have reported that the addition of DWI sequence can be of value for the evaluation of patients with PDAC, especially improving the staging; nevertheless, it is still unclear whether and how DWI could be helpful for identification, characterization, prognostic stratification and follow-up during treatment. The aim of this paper is to review up-to-date literature data regarding the applications of DWI and IVIM to PDACs.

Key words: Pancreas; Pancreatic neoplasms; Pancreatic ductal carcinoma; Magnetic resonance imaging; Diffusion magnetic resonance imaging

© The Author(s) 2015. Published by Baishideng Publishing

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Group Inc. All rights reserved.

Core tip: Diffusion-weighted imaging (DWI) plays an important role for the identification of pancreatic adeno-carcinoma, even if small in size, thus allowing early diagnosis. The intravoxel incoherent motion model is a promising DWI technique for the characterization of this tumor, with potential usefulness for the differenti-ation from mass-forming pancreatitis. Thanks to its high negative prognostic value, DWI should be used to assess the presence of liver metastases in patients with pancreatic adenocarcinoma.

De Robertis R, Tinazzi Martini P, Demozzi E, Dal Corso F, Bassi C, Pederzoli P, D'Onofrio M. Diffusion-weighted imaging of pancreatic cancer. World J Radiol 2015; 7(10): 319-328 Available from: URL: http://www.wjgnet.com/1949-8470/full/v7/i10/319.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.319

INTRODUCTIONMagnetic resonance imaging (MRI) has a well-esta-blished role in the evaluation of patients with pancreatic ductal adenocarcinoma (PDAC). MR diffusion-weighted imaging (DWI) is a relatively recent technological improvement of MRI. DW sequence can evaluate the diffusion of water molecules (Brownian motions) within biological tissues: All factors that tends to narrow the extracellular compartment or modify water exchanges through cell membranes lead to an impairment of the diffusion of water molecules. Tissues with restriction of water diffusion present high signal intensity on DW images and low signal intensity on the apparent diffusion coefficient (ADC) map; diffusion restriction can be also quantified through the calculation of the ADC value within specific regions of interest (ROIs).

Thanks to technological improvements that have shortened the acquisition time and improved the signal-to-noise ratio, DWI sequence has been widely adopted as a part of abdominal MRI examination protocols. Several authors have assessed the usefulness of this technique for the evaluation of PDAC and have reported that the addition of DWI sequence might represent an adjunct value, especially improving the staging. Nevertheless, it is still unclear whether and how DWI could be of value for identification, characterization, prognostic stratification and post-treatment follow-up of these patients.

The aim of this paper is to describe the applications of DWI to the evaluation of patients with PDAC, in parti-cular regarding lesion identification, characterization, prognostication and assessment of response to therapy, through a review of up-to-date literature data.

DWI: TECHNICAL BASESIn 1965, Stejskal and Tanner[1] developed a modified

T2-weighted MRI sequence that included motion-probing gradients for the detection of the diffusion of water molecules. DWI enables the visualization of Brownian random molecular motions in the extracellular and intracellular spaces[2]. This technique can provide information on the cellular density and the integrity of cell membranes, since the degree of restriction to water diffusion in biologic tissues is inversely correlated to these features[3-6]. Nevertheless, any factor that modifies the extracellular space (fibrosis, edema, size of the cells, size and density of intratumoral vessels) may also contribute to diffusion restriction.

The first clinical application of DWI has been the evaluation of the hyperacute phase of brain ischemia. Cytotoxic edema induced by ischemia and neuronal death narrows the extracellular space and therefore decreases the diffusion of water molecules. Thereafter, DWI has been proven to be useful for the assessment of a variety of intra-cranial pathologic conditions, as tumors. High cellular density, which is typical of tumors, narrows the extracellular space and determines a high density of hydrophobic cellular membranes[7], leading to impaired diffusion of water molecules.

Technical advances, as the use of parallel imaging techniques, have shortened the acquisition time and have improved the contrast- and signal-to-noise ratio of this sequence, thus leading to an increased use of DWI in the MR evaluation of the abdomen[8].

The acquisition technique and parameters may vary from institution to institution. The choice of acquisition using free-breathing, respiratory-triggering, navigator-tracking, or breath-hold is optional; nevertheless, this selection may influence image quality and acquisition time: Free-breathing acquisition provides lower image quality, but the acquisition time is invariably shorter as compared to respiratory-gated acquisitions. Free-breathing DWI acquisition is therefore more widely used for “work horse” MRI abdominal protocols.

The b-value is a technical parameter that regulates the strength, duration and interval of bipolar motion-probing gradients and affects the degree of phase dispersion and the diffusion weighting of the images. DW images are acquired using at least two different b-values, both low (for example, 0 or 50 s/mm2) and high (for example, 800 or 1000 s/mm2). Changing the b-value leads to a variation of the sensitivity of the DW sequence to water motion[2]. At low b-values, lesions with high diffusion (e.g., cysts) appear hyperintense compared to the surrounding tissues, since the T2-weig-hted contrast is still dominant. Increasing the b-value leads to a signal loss of tissues with ‘‘free diffusion’’ (i.e., cysts, cerebro-spinal fluid, necrosis), whereas tissues with restricted diffusion, as solid neoplastic areas, will appear hyperintense.

Low b-value images have generally higher spatial resolution and better image quality, being comparable to T2-weighted fat-suppressed images, while high b-value images have higher contrast resolution, but

De Robertis R et al . Diffusion-weighted imaging of pancreatic cancer


lower spatial resolution.The ADC quantifies the diffusion of water molecules

and can be represented with the ADC map. The evaluation of the ADC map is mandatory: Hyperintense areas on both high b-value DW image and the ADC map are typical of tissues with “T2-shine through” effect, that occurs because of long T2 decay time in some cases, as for example subacute infarction with vasogenic edema or epidermoid cysts. In contrast, areas with restricted water diffusion will appear hyperintense on high b-value DW image and hypointense on ADC map. Beyond the visual assessment there is also the possibility of a quantitative analysis by the calculation of the ADC value, which can be measured drawing ROIs within the target tissue; ADC measurement can be expressed as a mean value or as a histogram representing the distribution of different ADC values within the ROI.

The ADC is a combined measurement of all mole-cular random movements of water molecules (diffusion) and blood microcirculation in the capillaries (perfusion)[9]. The intravoxel incoherent motion (IVIM) model takes these two sources of signal decay into account, thus providing a separate quantification of diffusion (provided by the diffusion coefficient - D and the pseudodiffusion coefficient - D*) and perfusion (represented by the perfusion fraction - f) parameters[10]. IVIM can therefore quantify the relative contribution of these parame-ters to the total diffusion restriction and can evaluate perfusional features without the need of contrast medium injection. IVIM acquisition needs in most cases respiratory compensation, and therefore this sequence has a long acquisition time. For this reason, the IVIM model is not completely integrated into clinical practice.

IDENTIFICATIONThe sensitivity of computed tomography (CT) in revealing PDAC is high, ranging between 89% and 97%[11]. MRI offers better soft tissue contrast com-pared with CT; PDACs are usually well recognized on T1-weighted and DW images, owing to differences between the histological components of the tumor and the circumstant parenchyma. There is however no significant diagnostic advantage of MRI over contrast-enhanced CT for the identification of PDAC[12].

Studies on DWI revealed that this sequence might have an important role in the identification of PDAC. Both visual analysis[13-15] and ADC measurement[14,16-21] can reliably distinguish PDAC from the background pancreatic parenchyma. Pancreatic tumors, even if small in size, almost invariably show diffusion restriction, as revealed by studies conducted on neuroendocrine tumors[22], presenting as a focal hyperintense area on high b-value DW images with hypointensity on ADC map[13].

Identification of PDAC can be therefore improved by the use of DW images, as tumors are brighter than the circumstant pancreatic parenchyma: The high contrast

resolution of high b-value DW images usually leads to a clear identification of these tumors.

PDACs present lower ADC values than the cir-cumstant parenchyma. Nevertheless, it is still unclear which is the histological component that mainly contrib-utes to diffusion restriction in PDACs. Lemke[23] reported that the IVIM-derived f value (perfusion fraction), which reflects blood microcirculation, was significantly lower in PDACs than in the healthy pancreas (mean, 8.59% ± 4.6% vs 25.0% ± 6.2%, respectively): This may be related to the histological composition of PDAC, which is mainly composed by fibrotic stroma with very few vessels.

The best way to reduce mortality in patients with PDAC is through early diagnosis, that necessary de-rives from an improvement of the identification of this tumor. This is of particular importance in high-risk patients (i.e., those with familiarity). At this regard, Del Chiaro et al[24] reported the efficacy of a MRI-based screening program in individuals at risk. Unfortunately, this study did not report the accuracy of DWI in PDAC detection; nevertheless, it could be argued that the high contrast resolution of DW images may help in the early identification of PDACs in high-risk patients.

Some authors reported that small or well-differ-entiated PDACs may lack typical CT features, as ill-defined margins and hypovascularity, and could therefore be missed or misdiagnosed[25]. Prokesch et al[26] emphasized that indirect signs such as mass effect, atrophic distal parenchyma, and interrupted duct sign were important indicators of the presence of tumors with no visible tumor–pancreas contrast. MRI could be helpful in these cases. Some old studies have suggested that T1-weighted spin-echo images with fat suppression and dynamic gradient-echo MR images enhanced with gadolinium could be superior to CT for detecting small pancreatic carcinomas[27,28]. At present, no single study evaluated the efficacy of DW images in the identification of small PDACs; nevertheless, as high b-value DW images provide high contrast resolution, this sequence is probably of value in this regard.

Chronic pancreatitis may represent a confusing factor for PDAC identification, as both T1-weighted and DW images may fail to discriminate between fibrotic parenchyma and the tumor, which typically contains large amount of fibrotic tissue. At this regard, Fukukura[29] reported that visual assessment of DW images might be misleading in these patients, as chronic inflammation frequently appears hyperintense on high b-value images. Despite this, the mean ADC value of PDACs (1.160 ± 0.22 × 10-3 mm2/s) was significantly lower than that of the pancreatic parenchyma affected by chronic pancreatitis (1.24 ± 0.23 × 10-3 mm2/s, P = 0.004). ADC quantification can be therefore helpful when the visual assessment is doubtful but clinical setting (presence of painless jaundice, newly onset diabetes or high CA 19.9 serum levels) or MRI features are highly suspicious for a PDAC associated with chronic



PDAC, solid pseudopapillary tumors and neuroendocrine tumors (PanNETs). Barral et al[19] and Lee et al[33], instead, did not reported significant differences in ADC values between PDACs and other solid pancreatic tumors.

IVIM-derived parameters may be helpful for charac-terization. Kang et al[34] found that perfusion-related parameters as f (perfusion fraction) were significantly lower in PDACs as compared to normal pancreas, chronic pancreatitis, and PanNETs. Concia et al[35] reported that PDACs are characterized by very low ADC0,50 and f values, significantly different from PanNETs and chronic pancreatitis. These findings are consistently related to the histologic nature of PDACs, which are fibrous tumors with very few internal vessels, as compared to the healthy parenchyma and to PanNETs.

The possibility to differentiate mass-forming inflam-matory diseases from PDAC by means of DWI is a topic of particular interest. These entities frequently present overlapping features at conventional MRI evaluation. Overall, mass-forming pancreatitis (MFP) and autoim-mune pancreatitis (AIP) tend to present lower ADC values than PDACs; nevertheless, literature data are inhomogeneous and controversial[18,36-43]. Details regar-ding the main published studies dealing with this issue are reported in Table 2. A meta-analysis by Niu et al[43], which included 9 studies, reported a pooled sensitivity and specificity of 86% and 82%, with an AUC of 0.91, for the differentiation between PDAC and MFP using DWI alone.

IVIM-derived parameters may be helpful for this differentiation. Lee et al[33] reported that ADC500, ADC1000, and D of MFP were all significantly lower than those of pancreatic cancer. Klauss et al[41] found that F (perfusion fraction) values were significantly higher in focal pancreatitis (16.3%) compared with PDACs (8.2%): This was explained by the increasing perfusion effects at lower b-values, which were correlated with a relatively higher vascularity in pancreatitis.

The comparison of ADC values of focal pancreatitis and pancreatic carcinoma to the remaining pancreas may be helpful for the differentiation of these diseases: Fattahi et al[42] reported that ADC values of focal panc-

pancreatitis.Some technical aspects should be considered

regarding PDAC identification using DWI. Respiratory-triggered acquisitions provide higher spatial resolution and signal-to-noise ratio compared to free breathing and breath-hold acquisitions, as reported by Kartalis et al[30]. As previously stated, respiratory-gated acquisition of DW images is time-consuming and is not frequently performed during clinical practice. Contrast medium administration does not induce modifications of DWI features: Liu et al[31] reported no significant differences in ADC measurements when comparing precontrast to postcontrast DWI acquired 6-7 min after contrast medium administration.

Summarizing, it seems that CT and conventional MRI sequences have a similar accuracy for PDAC identification in most cases; further studies should be performed to assess the efficacy of DW images in identification of small/well differentiated PDACs.

CHARACTERIZATION Pancreatic adenocarcinoma is usually hypointense to the normal pancreas on T1-weighted fat-suppressed sequences, shows hypoenhancement during arterial phase, and shows progressive enhancement on delayed sequences. These features, and particularly the hypointense appearance on pancreatic phase images, are distinctive of this tumor[32]. Very few studies have focused on the role of DWI for the differential diagnosis of solid pancreatic tumors. Literature data reveal that quantitative analysis of DW images can distinguish between benign and malignant pancreatic lesions[19]. Nevertheless, ADC quantification could fail in the differentiation of solid pancreatic lesions, due to a wide overlap in ADC values[18-20,33]. Details regarding ADC quantification of pancreatic solid neoplasms are reported in Table 1. Yao et al[18] reported that ADC measurement using respiratory-triggered DWI at 3. T may aid to disclose the histopathological pattern of normal pancreas and solid pancreatic masses, which may be helpful in characterizing solid pancreatic lesions: statistical difference was noticed in ADC values among


Ref. No. of patients Field strength (T) b -values(s/mm2)

Mean ± SD ADC values(× 10-3 mm2/s)

P value

Yao et al[18] 30 PDACs 3 0, 600 1.57 ± 0.26 < 0.00112 SPTs 1.05 ± 0.35

15 PanNETs 1.62 ± 0.41Barral et al[19] 18 malignant1 1.5 0, 400, 800 1.1502 < 0.05

10 benign 2.4932

Lee et al[33] 47 PDACs 1.5 0, 500, 1000 1.23 ± 0.18 NS6 SPTs 1.16 ± 0.36

5 PanNETs 1.30 ± 0.41

Table 1 Comparison of apparent diffusion coefficient values between different solid pancreatic neoplasms

1Including 13 PDACs; 2Median. T: Tesla; ADC: Apparent diffusion coefficient; PDAC: Pancreatic ductal adenocarcinoma; SPT: Solid pseudopapillary tumor; PanNET: Pancreatic neuroendocrine tumor; NS: Not statistically significant.


reatitis (2.09 × 10-3 mm2/s) were indistinguishable compared with those of the remaining pancreas (2.03 × 10-3 mm2/s), which suggests that the same inflammatory process may be present both in focal pancreatitis and the remaining pancreas; instead, ADC values of pancreatic carcinoma (1.46 × 10-3 mm2/s) were invariably lower than those of the remaining pancreas (2.11 × 10-3 mm2/s).

Summarizing, it seems that DWI can distinguish between benign and malignant solid pancreatic lesions. Despite this, quantitative analysis of DWI features can fail in the differentiation between solid pancreatic tumors due to a wide overlap of ADC values. DWI may be potentially feasible for differentiating PDAC from MFP, especially using the IVIM technique. However, large-

scale randomized control trials are necessary to assess its real clinical value.

PROGNOSTIC STRATIFICATIONPrognosis in patients with PDAC is influenced by the histopathologic grade. Nevertheless, it plays a less important role in clinical management of PDACs as compared to the stage of the disease.

Some studies tried to correlate DWI findings with the histopathologic features of PDACs[20,21,44-48]; literature data dealing with this specific topic are reported in Table 3. Ideally, well-differentiated PDACs should present higher ADC values as compared to low-grade tumors, but some authors reported opposite findings



Mean ± SD ADC values(× 10-3 mm2/s)

P value

Yao et al[18] 30 PDACs 3 0, 600 1.57 ± 0.26 < 0.00115 MFPs 1.19 ± 0.15

Barral et al[19] 13 PDACs 1.5 0, 400, 800 1.150 NS8 MFPs 1.160

Lee et al[33] 47 PDACs 1.5 0, 500, 1000 1.46 ± 0.20/1.23 ± 0.181 < 0.0513 MFP 1.23 ± 0.22 /1.04 ± 0.181

Hur et al[36] 28 PDACs 1.5 or 3 0, 500 1.512 < 0.059 AIPs 1.086

Ma et al[37] 25 PDACs 3 0, 800 1.39 ± 0.22 < 0.0514 MFPs 1.21 ± 0.23

Huang et al[38] 37 PDACs 3 0, 1000 1.06 ± 0.15 < 0.0514 MFPs 1.35 ± 0.14

Kamisawa et al[39] 40 PDACs 1.5 800 1.249 ± 0.113 < 0.00113 AIPs 1.012 ± 0.112

Wiggermann et al[40] 24 PDACs 1.5 50, 500 0.78 ± 0.11 NS20 MFPs 0.69 ± 0.18

Klauss et al[41] 20 PDACs 1.5 Multiple2 2.55 ± 1.09/1.46 ± 0.311 < 0.059 MFPs 3.17 ± 0.67/1.76 ± 0.191

Fattahi et al[42] 10 PDACs 1.5 0, 600 1.46 ± 0.18 NE14 MFPs 2.09 ± 0.18

1Two readers; 20, 25, 50, 75, 100, 150, 200, 300, 400, 600, 800 s/mm2. PDAC: Pancreatic ductal adenocarcinoma; MFP: Mass-forming pancreatitis; AIP: Autoimmune pancreatitis; NE: Not evaluated; NS: Not statistically significant.

Table 2 Comparison of apparent diffusion coefficient values between pancreatic ductal adenocarcinomas and mass-forming pancreatitis/autoimmune pancreatitis


Mean ± SD ADC(× 10-3 mm2/s)

P value

Wang et al[20] 21 1.5 0, 500 2.10 ± 0.42 (MD-WD) < 0.051.46 ± 0.17 (PD)

Legrand et al[21] 22 1.5 or 3 Multiple1 1.43 ± 0.12 (WD) 0.05 1.94 ± 0.62 (MD-PD)

Muraoka et al[44] 10 1.5 0, 500 1.88 ± 0.39 (loose fibrosis) < 0.05 1.01 ± 0.29 (dense fibrosis)

Rosenkrantz et al[45] 30 1.5 0, 500 1.78 ± 0.33/1.75 ± 0.49 (MD-WD)2 NS 1.69 ± 0.36/1.62 ± 0.33 (PD)2

Fukukura et al[46] 92 3 0, 1000 1.10 ± 0.09 (high cellularity) < 0.05 1.25 ± 0.18 (low cellularity)

Table 3 Data derived from studies that have evaluated apparent diffusion coefficient quantification of pancreatic ductal adenocarcinomas with different degree of differentiation

10, 50, 200, 400, 600, 800 s/mm2; 2Two readers. T: Tesla; WD: Well differentiated PDAC; MD: Moderately differentiated PDAC; PD: Poorly differentiated PDAC; ADC: Apparent diffusion coefficient; PDAC: Pancreatic ductal adenocarcinoma; NS: Not statistically significant.


as well as non-significant results. It is reasonable to believe that the main contribution to the restriction of water diffusion in PDACs is provided by fibrosis, which is the predominant part of this tumor, while the contribution of the cells - even if less differentiated - and the perfusion effect provided by blood vessels should be minimal. Wang et al[20] reported that PDACs characterized by dense fibrosis have significantly lower ADC values compared to those characterized by abundant neoplastic tubular structures; moreover, well/moderately differentiated PDACs with dense fibrosis showed also significantly lower ADC values than those with loose fibrosis. Muraoka et al[44] reported similar findings: In their study, the mean ADC value was significantly higher in PDACs with loose fibrosis (1.88 ± 0.39 × 10-3 mm2/s) than in those with dense fibrosis (1.01 ± 0.29 × 10-3 mm2/s, P < 0.05). Moreover, Rosenkrantz et al[45] did not report significant difference in mean ADC between poorly and well/moderately differentiated tumors. Unfortunately, these findings have not been confirmed by other studies. Legrand et al[21], for example, reported that mean ADC values did not differ significantly between tumors having < 50% of fibrotic stroma and those having > 50% of fibrotic stroma (P = 0.94), or between tumors containing dense fibrosis and those containing loose fibrosis (P = 0.81). Regarding IVIM, Klauss et al[47] reported that the difference between the IVIM-derived D value between PDACs with moderate and severe fibrosis was significant, with a respective mean value of 1.02 ± 0.48 × 10-3 mm2/s and 1.22 ± 0.76 × 10-3 mm2/s, but the cellular complexes surrounded by fibrosis provided more structural limitations than did fibrosis alone.

Some authors have proposed a more practical role for DWI, testing correlations with clinical features or outcomes (e.g., tumor stage, aggressiveness, or survival) rather than the histopathologic grade. Hayano et al[48] reported a significant negative correlation between ADC and tumor size (r = -0.59, P = 0.004) and the number of metastatic lymphnodes (r = -0.56, P = 0.007). Tumors with low ADC values had a significant higher tendency to show portal system and extra-pancreatic nerve plexus invasion (P = 0.04 and 0.01, respectively) than those with high ADC. On the contrary, Rosenkrantz et al[45] did not report significant difference in mean ADC between tumors with stage T3 vs stage T1/T2, or between tumors with and without metastatic peri-pancreatic lymph nodes. Fukukura et al[46] reported that the median ADC value of PDACs was not associated with significantly differences in survival (P < 0.001 for all phases).

It is therefore still unclear whether DWI could be helpful in PDAC prognostication; overall, ADC values tend to be low in less differentiated lesions. Moreover, it seems that PDACs with low ADC values tend to have a worse clinical course and prognosis than PDACs with high ADC values. Larger studies, particularly regar-ding IVIM-DWI, are needed to further evaluate these findings.

STAGINGAbout 80% of PDACs are unresectable at diagnosis, due to a locally advanced disease or to the presence of liver metastases: M+ stage precludes most treatments beyond chemotherapy. The detection of liver metas-tases is related to their size. The lower size threshold of conventional imaging techniques for the detection of metastases lays around 1 cm[49]; unfortunately, postmortem studies has shown that the ratio between metastases larger than 1 cm and those smaller than 1 cm is approximately 1:4[50]. These findings clearly indicate that imaging should have a capacity to detect and characterize metastases smaller than 1 cm. A meta-analysis by Niekel et al[51] reported sensitivity estimates of CT, MR, and FDG-PET on a per-lesion basis of 74.4%, 80.3%, and 81.4%, respectively, whereas on a per-patient basis, the sensitivities of CT, MR, and FDG-PET were 83.6%, 88.2%, and 94.1%, respectively. For lesions smaller than 10 mm, the sensitivity estimates for MR were higher than those for CT.

DWI is a reliable method to detect liver metastases, with a sensitivity and specificity higher than both CT and conventional MR sequences[51], even though most published studies comprised a small amount of patients with metastatic PDAC. DWI sensitivity and specificity in detecting liver metastases can reach respectively 90.8% and 97.5%[51-55]. Moreover, DW sequences are able to detect focal liver lesions even down to 3 mm, as reported in a study by Coenegrachts et al[56]. Some authors have pointed out that DWI alone should not be used for the diagnosis of liver metastases because of possible false positives; the overlap in ADC values among benign and malignant hepatic lesions strengthen this consideration. Whenever possible, MR findings obtained during the hepatobiliary phase after hepatocyte-specific contrast media administration, should be used in association with DW images to obtain a definite diagnosis[55-60].

Preoperative assessment of the N stage can be very difficult using MRI. The presence of diffusion restriction in multiple peri-pancreatic lymph nodes is not uncommon in patients with PDAC. Moreover, mic-roscopic nodal metastases are frequently found in small peri-pancreatic lymphnodes at histopathological analysis[61,62]. A study by Imai et al[63] reported that, despite a low sensitivity, the specificity and accuracy for the detection of para-aortic lymph node metastases from PDAC were relatively high for MRI (96.8% and 88.4%, respectively); unfortunately, their protocol did not include DWI sequence. Literature data suggest that DWI is a good method for the detection of nodal metastases, at least when applied to pelvic, breast, and head/neck tumors[64-66]; these favorable results may be assumed to be applicable also to PDACs. Unfortunately, studies on diagnostic accuracy of DWI are difficult to perform, mainly because extended lymphadenectomy is not routinely performed during pancreatic resection[61,62]. Data regarding ADC measurement for the distinction



between inflammatory and metastatic lymphnodes are controversial[67-71]. Further studies should be therefore performed to assess the usefulness of DWI for the detection of nodal involvement by PDAC.

Several authors have reported the usefulness of DWI to diagnose peritoneal implants, but these studies included a small amount of patients with PDAC. Bozkurt[72] reported that the association of DW images and conventional MRI images had 83% sensitivity, 94% specificity, and 86% accuracy for the diagnosis of peritoneal implants. Low et al[73] reported high sensitivity and accuracy values when DWI was added to conventional MRI sequences for the detection of peritoneal implants.

DWI should be therefore ideally evaluated for first during the staging of patients with PDAC. In most cases, if no focal liver lesions are detected using DWI, then the presence of liver metastases is extremely unlikely, thanks to its high negative predictive value. Nevertheless, conventional sequences should be always taken into consideration, due to possible false positive results of DWI.

POST-TREATMENT FOLLOW-UPDWI can depict microstructural changes during therapy. Niwa et al[74] reported differences in ADC values among patients with advanced pancreatic cancer treated with gemcitabine: ADC values were significantly different between the progressive and stable groups at 3 mo’ and 6 mo’ follow-up (P = 0.03 and P = 0.04, respectively). The rate of tumor progression was significantly higher in those with a low b-value (400 s/mm2) ADC than in those with a high b-value ADC (median progression time, 140 d vs 182 d, P = 0.01).

Cuneo et al[75] reported a significant correlation between pre treatment mean ADC values of resectable PDACs and the amount of tumor cell destruction after chemoradiation evaluated on surgical specimens, with a Pearson correlation coefficient of 0.94 (P = 0.001). Mean pre-treatment ADC was 1.61 × 10-3 mm2/s in responding patients (> 90% tumor cell destruction) compared to 1.25 × 10-3 mm2/s in non-responding patients.

Overall, a very limited number of studies focused on the post-treatment DWI assessment of PDACs. This topic deserves further studies in order to establish the real usefulness of DWI for early assessment of chemotherapy outcome.

CONCLUSIONDWI is a robust imaging technique that should be performed during MRI evaluation of PDACs. The high contrast resolution of PDACs on DW images is useful for the identification of even very small lesions, thus allowing earlier diagnosis. IVIM, although not fully integrated into clinical practice, represent a promising DWI technique for characterization of PDACs, with particular interest on

the differentiation between PDACs and MFPs. Considered its high negative prognostic values, DWI findings should be considered for the staging of patients with PDAC. Further studies are needed to evaluate the usefulness of DWI for treatment monitoring.

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P- Reviewer: Gonzalez-Reimers E, Guan YS, Ranieri G S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK



nervous system abnormalities, referring particularly to embriyological aspect as a consequence of any of the three developmental stages, i.e. , cell proliferation, cell migration and cortical organization. These include cotical dysgenesis, microcephaly, polymicrogyria, schizencephaly, lissencephaly, hemimegalencephaly, heterotopia and focal cortical dysplasia. Since magnetic resonance imaging is the modality of choice that best identifies the structural anomalies of the brain cortex, we aimed to provide a mini review of MCD by using 3T magnetic resonance scanner images.

Key words: Cortical development; Cortical dysplasia; Lissencephaly; Malformation; Polymicrogyria; Magnetic resonance imaging


Core tip: Malformations of cortical development reflect embryological disruptions in neuronal proliferation, neuronal migration, cortical organization or multiple steps of the cortical development. Malformation of cortical development (MCDs) are important causes of refractory epilepsy. Magnetic resonance imaging including the advanced MRI techniques has a pivotal role in diagnosis of MCDs and prediction of feasibility of surgical management in cases that are refractory to medication.

Battal B, Ince S, Akgun V, Kocaoglu M, Ozcan E, Tasar M. Malformations of cortical development: 3T magnetic resonance imaging features. World J Radiol 2015; 7(10): 329-335 Available from: URL: http://www.wjgnet.com/1949-8470/full/v7/i10/329.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.329

INTRODUCTIONMalformations of cortical development (MCDs) are a

Malformations of cortical development: 3T magnetic resonance imaging features

Bilal Battal, Selami Ince, Veysel Akgun, Murat Kocaoglu, Emrah Ozcan, Mustafa Tasar

Bilal Battal, Selami Ince, Veysel Akgun, Murat Kocaoglu, Emrah Ozcan, Mustafa Tasar, Department of Radiology, Gulhane Military Medical School, 06018 Etlik, Ankara, Turkey

Murat Kocaoglu, Department of Radiology, Near East University, Faculty of Medicine, Nicosia, North Cyprus, Turkey

Author contributions: Battal B, Ince S, Akgun V, Ozcan E and Kocaoglu M designed and collected data; Battal B, Ince S and Akgun V written of the article; Battal B, Kocaoglu M and Tasar M reviewed and supervised the manuscript.

Conflict-of-interest statement: The authors declare no conflict of interests.


Correspondence to: Bilal Battal, MD, Department of Radiology, Gulhane Military Medical School, General Doktor Tevfik Saglam Caddesi, 06018 Etlik, Ankara, Turkey. [email protected]: +90-533-4330667Fax: +90-312-3260551

Received: April 26, 2015 Peer-review started: May 11, 2015First decision: June 24, 2015Revised: July 31, 2015 Accepted: August 20, 2015Article in press: August 21, 2015Published online: October 28, 2015

Abstract Malformation of cortical development (MCD) is a term representing an inhomogeneous group of central

MINIREVIEWS






complex group of abnormalities that may occur due to interruption the stages of proliferation, migration or postmigrational development of cortex. MCDs are common and important cause of seizures particularly in children. MCDs may result from lack of migration, over migration or ectopic migration of immature neurons[1]. Magnetic resonance imaging (MRI) is the modality of choice that allows diagnosis of MCDs and correlation between radiologic and clinicopathologic findings related to MCDs[2]. New techniques such as functional MRI (fMRI), MR spectroscopy and diffusion tensor imaging (DTI) are useful particularly for the detection of small sized or subtle MCDs[2]. Barkovich et al[3] described the latest updated version of classification scheme for MCDs in 2012.

In this mini-review article, we discuss different types of cortical malformations in terms of their MRI characteristics. We illustrate their imaging features with emphasis on lesion location and direction of extension.

ADVANCED MRI IN MCDMRI is the preferred imaging technique for deter-mination and detailed assessment of MCD, with detailed information available from ultimate MR sequences and modalities. Advanced MRI sequences and tech-niques including volumetric three-dimensional (3D) gradient recalled echo (GRE) T1-weighted sequences, volumetric fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), MR spectroscopy, fMRI and DTI have improved image quality and have been helpful in detection and characterization of MCDs and detailed evaluation of its extent and relationship with the surrounding white and gray matter areas.

Volumetric 3D GRE T1-weighted sequences allow high resolution multiplanar reformatted images, and support accurate diagnosis and detailed evaluation. For this purpose, slices of 1 mm thickness are gained with isotropic voxels. This allows high spatial resolution, more detailed evaluation of cortical thickness and morphology, and gray-white matter differentiation in three orthogonal planes in a reasonable time frame for clinical use. Volumetric FLAIR sequence may be useful in the determination of small signal changes and correct delineation of the borders of MCD and related signal changes, especially in 3T. SWI is a new, full-velocity-compensated high-resolution 3D GE sequence, useful for the evaluation of various pathologies characterized with punctate hemorrhages and calcification in brain parenchyma[4,5].

Metabolic components of the brain tissue can be determined by proton MR spectroscopy in vivo. Simister et al[6] reported that large cortical malformations had abnormal levels of both glutamate + glutamine and gamma-aminobutyric acid. Low N-acetylaspartate (NAA) and high choline (Cho) levels were also observed. They concluded that MCD showed spectroscopic features of primitive tissue and abnormal metabolisms of both

inhibitory and excitatory neurotransmitters. MR spectro-scopy technique demonstrated that MCD extends beyond the borders determined by the conventional MR imaging, even with sophisticated volumetric techni-ques[7,8]. In a phosphorus MR spectroscopic study, Andrade et al[9] demonstrated widespread acidosis in the normal appearing parenchyma, and they con-cluded that visible lesions of the MCD are only the tip of the iceberg. MR spectroscopy examination can also be useful in differentiating low-grade tumor from focal cortical dysplasia (FCD) based on imaging can be challenging but important for treatment planning. The main difference was low level of NAA in gliomas compared to nearly normal levels of NAA in FCD and dysembryoplastic neuroectodermal tumor (DNET). In contrast, there were increased Cho levels in low-grade glioma compared to FCD.

fMRI can localize brain functions based on changes in blood flow and its data can be used in pre-surgical mapping. For the functional evaluation of the MCD, simple (sensomotor, visual) or complex (language, memory) fMRI paradigms can be used. fMRI technique can visualize the functions of the MCDs and their relationship to the eloquent cortex, and can provide important information to surgeons prior to epilepsy surgery[10].

DTI gives microstructural data about tissues and provides further information on brain tissue that cannot be obtained by using conventional MR sequences. Microstructure of the tissue may change due to incre-ase or decrease of neuronal cell volume, enlarged or reduced extracellular space and tissue damage, thus altered diffusion and fractional anisotropy may occur[11]. MCD have features of loss of tissue organization and abnormalities of neuronal structure, but preserved normal cellular density. Therefore, reduced anisotropy but normal diffusivity values similar to the normal tissue are characteristic DTI findings of the MCD[12,13].

MALFORMATIONS OF CORTICAL DEVELOPMENT Disorders of proliferationCortical dysgenesis: Hemimegalencephaly is deter-mined as a cortical dysgenesis in this new classification[3]. Hemimegalencephaly is a hamartomatous malformation characterized by overgrowth of all or part of one cerebral hemisphere. Three different types are described. First type is isolated hemimegalencephaly, which is no hemicorporal hypertrophy and not associated with cutaneous or systemic involvement (Figure 1). Second type is hemimegalencephaly associated with various neurocutaneous syndromes such as neurofibromatosis type 1, epidermal nevus syndrome, proteus syndrome, and tuberous sclerosis and also typically including hemi-corporal hypertrophy of the ipsilateral part of the body. The last and the rarest one is total hemimegalencephaly associated with hypertrophy of the ipsilateral cerebellar

Battal B et al . Malformations of cortical development: MRI features


hemisphere and brainstem. The cerebral cortical structures may be normal or dysplastic[14,15].

Unlike other types of FCDs, FCD type Ⅱ (FCD-Ⅱ) is accepted in-group of cortical dysgenesis in the new classification of Barkovich et al[3] FCD-Ⅱ has divided into two subgroups as type a and b[16]. FCD-Ⅱ is characterized by focal area of cortical thickening, marked blurring of gray and white matter junction, and in some cases signal change in adjacent white matter on T2-weighted and FLAIR images[17]. On the other hand, it is harder to identify FCD-IIa than FCD-Ⅱb, and FCD-IIa cannot be always detected on MRI[16].

FCDs can mimic gliomas. FCD-Ⅱ often occurs in ex-tra-temporal location especially frontal region, whereas a temporal location suggests gliomas[18]. Since the cortical dysplasia primarily affect the gray matter and generally not associated with edema and gliosis, the increased signal on T2-weighted images is less distinct in FCDs when compared with the tumors (Figure 2). Gliomas may cause mass effect and frequently show intravenous contrast enhancement[1].

Microcephaly: Congenital microcephaly refers to a head circumference of patient < 3 standard deviation below normal for that age without history of intrauterine damage[1]. There is also another microcephaly entity, which is classified in abnormal postmigrational development group. This type patients born with normal or small head size, and severe microcephaly progresses within 1-2 years after the birth[3].

Microcephaly with a simplified gyral pattern is a mild form of microlissencephaly, and characterized with profound microcephaly, significantly decreased number of sulci, sulcation abnormality, but normal cortical thickness (Figure 3). This malformation is generally not associated with other congenital structural anomalies[1].

Disorders of migrationPeriventricular heterotopia (subependymal nodular): Heterotopia is an abnormal location of neu-

rons anyplace between the subependymal region of the lateral ventricles and cerebral cortex secondary to arrest of radial migration[1].

Periventricular (subependymal nodular) heterotopias are often bilateral and placed adjacent to the walls of the lateral ventricles, frequently in the peritrigonal regions, the temporal and occipital horns[1]. The chara-cteristic appearances of nodular heterotopia are small, round or oval shaped nodules isointense with gray matter on all MR sequences, located in subependymal layer, and do not show contrast enhancement (Figure 4). Periventricular heterotopia may project into the ventricular lumen (Figure 5)[1].

Subcortical heterotopia (Band heterotopia): Subco-rtical band heterotopias (SCH) are located within the subcortical or deep white matter between the ventricular epandimal surface and the cerebral cortex. SCH may be in various forms including nodular, curvilinear or mixed. Thin overlying cortex and shallow sulci are characteristic findings for SCH (Figure 6)[1,19].

SCH is a rare developmental malformation seen primarily in female and may be familial with X-linked dominant inheritance. On MRI, it shows a characteristic two parallel layers of gray matter separated by a thin white matter layer (3-layer cake: A thin outer ribbon, a very thin layer of white matter and a thick inner band (Figure 7)[1,19].

Lissencephaly: Lissencephaly is defined as smooth brain and characterized with the absent normal gyral and sulcal pattern of the brain. The neocortex of lissence-phalic patients lacks the normal cortical lamination and contains four layers instead of the six[19]. Classic or type 1 lissencephaly appears as a complete or incomplete agyria. The complete form is characterized with smooth surface of entire brain. In the incomplete form, which is more commonly seen type, temporal lobes and inferior regions of frontal lobes have some gyral formation (Figure 8). The important MRI findings of classical lissencephaly are hourglass configuration, thick cortex and thin subcortical white matter, pachygyria-agyria areas, lack of gray-white matter interdigitation, and shallow Sylvian fissure[1,19].

Cobblestone malformation: Cobblestone liss-encephaly or formerly called type 2 lissencephaly is characterized by a nodular cortical surface accompanied by ocular anomalies and congenital muscular disorders[1]. Cobblestone lissencephaly has been divided into three different groups based on severity: (1) Cobblestone lissencephaly occurs in various genetic conditions, with Walker-Warburg syndrome being the most severe form; (2) Fukuyama congenital muscular dystrophy, the mildest form; and (3) muscle-eye brain disease, the moderate form. Congenital muscular dystrophy is a key feature (Figure 9)[19].


Figure 1 A 10-year-old boy with hemimegalencephaly. Coronal T1-weighted magnetic resonance image shows hypertrophy of the left cerebral hemisphere, mild enlargement of the left lateral ventricle, hamartoma (white arrow) in postero-medial area of the right thalamus.


affected various degrees: Unilateral or bilateral; asym-metrical or symmetrical; single focal focus, multifocal, or diffuse. Around the Sylvian fissure, mostly posterior perisylvian area is the most common location (Figure 10)[21].

For identifying PMG the combination of three chara-cteristics on MR images has been used: (1) abnormal gyral pattern; (2) increased cortical thickness; and (3)

Disorders of postmigrational developmentPolymicrogyria: Polymicrogyria (PMG) is caused by an interruption in normal cerebral cortical development in the late neuronal migration or early postmigrational development periods[20]. The cortical surface appears thick and irregular or can have multiple small gyri separated by shallow sulci.

In the cases of PMG, the cerebral cortex may be


Figure 3 An 8-year-old girl with microlissencephaly. Axial T2-weighted images (A, B) show reduction in the number and depth of the sulcus, thickened cortex (white arrows) with choroidal fissure cyst (black arrow). Thinning of posterior parts of the corpus callosum is also seen on sagittal three-dimensional (3D) T1-weighted image (C).

A B C

Figure 2 Focal cortical dysplasia type IIb of the left frontal cortex in a 3-year-old girl. Axial T2-weighted (A) and coronal T1-weighted (B) magnetic resonance images reveal a slight increase of white matter signal on T2-weighted image, significant blurring on T1-weighted image in gray matter-white matter junction (arrow).

A B

Figure 4 An 18-year-old boy with subependymal heterotopia. Axial inversion recovery T1-weighted image shows gray matter nodules located adjacent to bilateral periventricular temporal horn region (arrows).

Figure 5 A 7-mo girl with subependymal heterotopia. Sagittal T1-weighted image shows gray matter nodule located in the periventricular region that protrudes into the ventricular wall (arrow).


irregularity of the cortical–white matter junction due to packing of microgyri[22]. These can be readily detected when thin sliced volumetric images are obtained[21].

Schizencephaly: Schizencephaly is characterized by unilateral or bilateral full thickness cleft that is extending from the subarachnoid spaces to the ventricular system, and lined with gray matter[23]. The cleft is often found in

perisylvian areas, and may be small (closed lip type) or large (open lip type)[24]. It may be associated with other malformations such as agenesis or dysgenesis of optic nerves, septum pellucidum (Figure 11), corpus callosum or hypocampus[25].

FCD: FCD type Ⅰ (FCD-Ⅰ) and type Ⅲ (FCD-Ⅲ) are


Figure 6 A 12-year-old boy with subcortical heterotopia. Sagittal 3D T1-weighted image shows large nodular form subcortical heterotopia (arrows) extends from the ventricle into the white matter in frontotemporal region.

Figure 7 An 8-year-old girl with subcortical heterotopia. Sagittal 3D T1-weighted image shows band heterotopia (double cortex) located between the ventricular wall and the cerebral cortex (arrows).

Figure 8 A 5-year-old girl with incomplete lissencephaly. Axial T1-weighted (A) and sagittal 3D T1-weighted (B) magnetic resonance images show pachygyria in frontotemporal region.

A B

Figure 9 An 18-year-old boy with cobblestone lissencephaly. Axial T2-weighted image (A) shows incomplete lissencephaly in right occipital region (white arrows). Sagittal 3D T1-weighted image (B) reveals multiple areas of shallow microgyri (black arrows) in the parietal and temporal lobes.

A B

A B

Figure 11 A 12-year-old boy with schizencephaly. T2-weighted coronal (A) and T1-weighted axial (B) images show oblique gray matter lined holohemispheric cleft (arrows) extending into the lateral ventricle that suggest open lip type schizencephaly with agenesis of septum pellucidum.


Figure 10 A 7-year-old boy with polymicrogyria. Axial 3D T1-weighted image shows bilateral perisylvian polymicrogyria (arrows).

in this group according to Barkovich et al[3] new MCD classification.

FCD-Ⅰ is a malformation presenting with abnormal cortical layering, either settle with radial cortical lamin-ation and maturation of neurons (FCD-Ⅰa) or the six-layered tangential cortical lamination of the neocortex (FCD-Ⅰb). The combination of these two subgroups is categorized as FCD-Ⅰc[16].

MRI examination of FCD-Ⅰ cases is usually normal[15]. Hippocampal atrophy is frequently coexistent with FCD-Ⅰ[17]. In some cases, prominent segmental or lobar hypoplastic/atrophic changes and decrease the volume of subcortical white matter (Figure 12), sulcal and gyral pattern abnormalities may be seen. The most common location of FCD-Ⅰ is the temporal lobe[1,17].

FCD-Ⅲ is divided into four subgroups; FCD-Ⅲa is in combination with hippocampal sclerosis. FCD-Ⅲb is associated with adjacent glial or glioneuronal tumors (i.e., DNET, ganglioglioma). FCD-Ⅲc is characterized with cortical lamination abnormalities adjacent to vascular malformations, whereas FCD-Ⅲd is associated with any other acquired lesions in early life period (i.e., post-traumatic lesions, ischemic injury, encephalitis)[3,16,17].

CONCLUSIONMCD are an inhomogeneous group of central nervous system abnormalities and their diagnosis during the routine clinical and radiologic practice ay be challenging. The suspicion of this kind of lesions arises when a sign is observed in clinical history, radiologic imaging or EEG findings. In some cases routine MRI scanning permit detection and definitive diagnosis of these pathologies. However, in most of the cases, careful evaluation of the MR imaging that contains some special sequences and special orientations are needed for definitive diagnosis and to determine the distribution and extent of MCD.

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11 Anderson AW, Zhong J, Petroff OA, Szafer A, Ransom BR, Prichard JW, Gore JC. Effects of osmotically driven cell volume changes on diffusion-weighted imaging of the rat optic nerve. Magn Reson Med 1996; 35: 162-167 [PMID: 8622579 DOI: 10.1002/mrm.1910350206]

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Figure 12 An 18-year-old girl with focal cortical dysplasia type Ⅰ. Axial fluid attenuated inversion recovery image shows blurring at gray-white matter junction with normal gray matter signal in the posterior of the left frontal lobe (arrows).


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P- Reviewer: Giovannetti G, Storto G S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK



Evaluation of primary adrenal insufficiency secondary to tuberculous adrenalitis with computed tomography and magnetic resonance imaging: Current status

Yu-Cheng Huang, Yu-Lian Tang, Xiao-Ming Zhang, Nan-Lin Zeng, Rui Li, Tian-Wu Chen

Yu-Cheng Huang, Yu-Lian Tang, Xiao-Ming Zhang, Nan-Lin Zeng, Rui Li, Tian-Wu Chen, Sichuan Key Laboratory of Medical Imaging, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China

Author contributions: Huang YC and Chen TW wrote the paper; Tang YL, Zhang XM, Zeng NL and Li R performed the collected the data.

Conflict-of-interest statement: Authors declare no conflicts of interest for this article.


Correspondence to: Tian-Wu Chen, MD, Sichuan Key Laboratory of Medical Imaging, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63# Wenhua Road, Nanchong 637000, Sichuan Province, China. [email protected]: +86-817-2262236Fax: +86-817-2222856

Received: April 12, 2015Peer-review started: April 13, 2015First decision: August 15, 2015Revised: August 25, 2015Accepted: September 10, 2015 Article in press: September 16, 2015Published online: October 28, 2015

AbstractAs one kind of infectious diseases of adrenal gland, adrenal tuberculosis can result in a life-threatening disorder which is called primary adrenal insufficiency (PAI) due to the destruction of adrenal cortex. Computed tomography (CT) and magnetic resonance imaging (MRI) play significant roles in the diagnosis of this etiology of PAI based on the CT and MRI appearances of the adrenal lesions. In this mini-review, we intend to study the CT and MRI features of adrenal tuberculosis, which could be helpful to both endocrinologist and radiologist to establish a definitive diagnosis for adrenal tuberculosis resulting in PAI.

Key words: Primary adrenal insufficiency; Tuberculosis; Adrenalitis; Computed tomography; Magnetic resonance imaging


Core tip: Adrenal tuberculosis is an important cause of the primary adrenal insufficiency (PAI) due to the destruction of adrenal cortex. Computed tomography (CT) and magnetic resonance imaging (MRI) play vital roles in the diagnosis of this etiology of PAI based on the CT and MRI appearances of the adrenal lesions. We herein discuss the CT and MRI technique, manife-stations, the role of CT and MRI in a definitive diagnosis for adrenal tuberculosis resulting in PAI.

Huang YC, Tang YL, Zhang XM, Zeng NL, Li R, Chen TW. Evaluation of primary adrenal insufficiency secondary to tuberculous adrenalitis with computed tomography and magnetic resonance

MINIREVIEWS






imaging: Current status. World J Radiol 2015; 7(10): 336-342 Available from: URL: http://www.wjgnet.com/1949-8470/full/v7/i10/336.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.336

INTRODUCTIONPrimary adrenal insufficiency (PAI), manifesting as clinically inadequate production or action of glucocorticoids, is a lifethreatening disorder when at least 90 percent of adrenal cortex has been destroyed[1,2]. As first depicted by Thomas Addison in 1855[3], the clinical manifestation of adrenal insufficiency were characterized by weakness, malaise, nausea, fatigue, anorexia and abdominal pain, together with orthostatic hypotension, constipation, weight losing, salt craving and characteristic hyperpigmentation of the skin[46]. The acute syndrome appears as a medical emergency since adrenal insufficiency may result in a severe hypotensive crisis and clouded sensorium[7]. But most of the symptoms are not so specific that may delay diagnosis.

Adrenal tuberculosis has been regarded as an important cause of PAI since the first reports by Thomas Addison[4,8]. During the past decades, incidence of adrenal tuberculosis has been greatly decreased due to the introduction of antituberculosis drugs. It is reported that PAI results from adrenal tuberculosis accounting for only 15%20% patients in developed countries[9]. However, adrenal tuberculosis is still the primary cause of PAI in developing countries[10].

In the traditional diagnostic workup for adrenal insufficiency, basal detection of cortisol and adrenocorticotropic hormone (ACTH) is sufficient for the diagnosis in most cases, but rarely the corticotropin test is required in primary failure[11]. To confirm or rule out adrenal insufficiency, plasma cortisol can initially be measured between 8 and 9 am[12]. The morning plasma cortisol concentrations of ≤ 3 μg/dL (83 nmol/L) are indicative of adrenal insufficiency, whereas concentrations of ≥ 19 μg/dL (525 nmol/L) rule out this disorder[13,14]. The patients with plasma cortisol concentrations of 319 μg/dL need the ACTH stimulation test. Additionally, basal plasma corticotropin should be measured in patients with possible PAI, and it can be found that plasma corticotropin concentrations invariably exceed 100 pg/mL (22 pmol/L), even though the plasma cortisol concentration is in the normal range[1]. As for the ACTH stimulation test, the corticotrophin should be given intravenously or intramuscularly, and the serum cortisol level is usually measured before injection of 250 μg corticotrophin, and 30 or 60 min after this injection[12,15]. Adrenal function is considered to be normal if the basal or the postcorticotropin plasma cortisol concentration is at least 18 μg/dL (500 nmol/L), or at least 20 μg/dL (550 nmol/L)[12]. Most physicians use the highest plasma cortisol value before or after the injection of corticotropin as the criterion of normality and not the absolute increase in plasma cortisol after this injection.

With the laboratory diagnostic procedures, however, the causes of PAI caused by infectious diseases such as tuberculous adrenalitis cannot be recognized for appropriately essential therapy. Computed tomography (CT) and magnetic resonance imaging (MRI) play significant roles in evaluation of this etiology because the CT and MRI appearances of the underlying diseases depend not only on the pathologic nature but also on the duration of the illness and the type of treatment[2,16,17]. Thus, we reviewed the CT and MRI features of tuberculous adrenalitis resulting in PAI for appropriate treatments.

CT TECHNIQUECT has been regarded as the modality of choice for identificating and characterizating tuberculous adrenalitis resulting in PAI[1822]. Prior to CT scan, opacification of the bowel should be carried out routinely with oral contrast materials, and 8001000 mL of 1% solution of sodium diatrizoate is used as oral contrast material in our hospital. To show the adrenal tuberculosis, 3 mm helical collimation with the field of view targeted to the adrenal gland and 3 mm reconstruction interval was recommended for clinical examination[18,23].

With the development of CT scanners, multidetector row CT (MDCT) has been used to depict the lesions of adrenal glands more and more frequently. In our institution, 16row MDCT (Aquilion, Toshiba Medical Systems, Tokyo, Japan) has been used to detect the adrenal tuberculosis. Owing to the improvement of spatial resolution, small adrenal lesions can be detected on images of multiplanar reformation[9]. Dualenergy CT was first utilized to evaluate the attenuation difference of adrenal lesions by Gupta et al[24].

There are two CT techniques including noncontrast and contrastenhanced CT. Noncontrast CT scan can be performed to illustrate the calcified tissue. For well depicting tuberculous adrenalitis in the majority of patients with adrenal insufficiency, the noncontrast CT examination should be followed by a contrast enhanced study, which is performed 6080 s after intravenously administrating 80100 mL of a contrast agent with 300 mg/mL of iodine at a rate of 3 mL/s by using a power injector.

MRI TECHNIQUEMRI has been proven useful for evaluating the adrenal glands due to its advantages of superior contrast resolution and tissue characterization potential[2528]. Body coil is used for both excitation and reception of MR signal. Adrenal MRI should include T1weighted axial images for showing the adrenal anatomy in detail, and T2weighted axial images for showing the lesions[29]. In our hospital, 1.5T and 3.0T MR scanners (Signa Excite; GE Medical System, Milwaukee, WI, United States) were used to detect the adrenal lesions, and adrenal MRI sequences include spinecho or flash T1

Huang YC et al . Tuberculous adrenalitis


weighted plain scan, and fast spinecho T2weighted scan. The adrenal MR images are acquired with a field of view of 3545 cm, and 58 mm contiguous slice thickness. Enhanced T1weighted images are acquired after intravenous administration of a bolus of 0.1 mmol/kg gadolinium diethylene triamine pentaacetic acid in our hospital. Because multiplanar imaging particularly including coronal section on all scanning series helps to detect extension of adrenal lesions into adjacent structures, the image planes are axial and coronal section on all scanning sequences at our institution. In addition, chemicalshift MRI with T1weighted inphase and outofphase gradientecho pulse sequences and gadoliniumenhanced images is of great importance to evaluate the adrenal lesions[30].

CT AND MRI MANIFESTATIONS OF ARENAL TUBERCULOSIS Adrenal tuberculosis occurs more commonly in bilateral glands (Figures 13) than in unilateral gland (Figure 4), and the occurrence of bilateral involvement is more than 80%[2,9,23,31]. This predominant anatomic distribution may be explained by the reason that either of adrenal glands can be susceptible to infection by tubercle bacilli from the primary infection via hematogenous or lymph routes in equal incidence[8]. The pathological changes of adrenal tuberculosis include tuberculous granuloma, caseous necrosis, fibrosis, cicatrix and calcification, and different CT and MR manifestations reflect the corresponding pathological changes.

Concerning on the adrenal contour, it varies during the courses of the adrenal tuberculosis. At early stage, the masslike enlargement of the adrenals with tuberculosis can be frequently found on CT and MRI (Figures 14), but the contour of adrenal glands preserve[2,9,23]. The radiologic appearances are pathologically based on the adrenals caseous necrosis area and tuberculous granuloma resulting from the destruction of the cortex by tuberculous mycobacteria[32]. The mean course might

be approximately 3 years after the infection[9,23].At late stage, the enlarged tuberculous adrenal

glands lessen or normalize pathologically in size or configuration due to the increase of fibrosis, fibrous cicatrix, and calcified tissue in the glands[8,32,33]. When the continuous antituberculosis therapy is subsequently performed, the initially enlarged adrenal glands with smooth rounded contours become small with irregular margins (Figure 2) on followup CT and MRI[8,9,23,32,3437]. The adrenal glands become atrophic, and the pathological mechanism can be that the gland tissue is almost completely substituted with fibrous tissue or calcification[2,3537]. In general, small or atrophic adrenals indicate tuberculosis with long duration of adrenal insufficiency or quiescent adrenal tuberculosis, whereas enlarged adrenals suggest adrenal tuberculosis at early stage or active adrenal tuberculosis[32,33,3841].

As for adrenal calcification, it may be diffuse, localized or punctuated, and its incidence increases with the course of adrenal tuberculosis. The calcification, predominantly occurring at late stage of tuberculosis, cannot be well illustrated on MRI but on CT, and the incidence of calcification is more than one half when the diagnosis of adrenal tuberculosis is made[33,41,42]. This manifestation may be due to the reason that the encapsulated granuloma becomes quiescent, and calcium salts deposit within the caseous regions at this stage[9,23].

Another manifestation of adrenal tuberculosis is the density and enhancement on CT, or the signal intensity and enhancement on MRI at different stages. At early stage, the enlarged adrenals (Figures 1, 2 and 4) demonstrate central low density or homogeneous density on noncontrast CT scans, and peripheral enhancement with low density in the central area is observed on the contrastenhanced scans in most of patients with adrenal tuberculosis[9,23,42]. On MRI, the involved adrenals (Figure 3) appear as hypointense or isointense on T1weighed images and hyperintense on T2weighted images, and the glands with caseous


Figure 1 A 53-year-old man who has fatigue, pigmentation of skin and loss weight in last five months with primary adrenal insufficiency due to adrenal tuberculosis. The unenhanced (A) and contrast-enhanced (B) CT scans reveal the mass-like enlargement of the bilateral adrenals with multifocal peripheral enhancement. CT: Computed tomography.

A B


The probability of the presence of peripheral rim enhancement decreases on enhanced CT and MRI with the decrease of granuloma and caseating necrosis at late stage[9,23]. In addition, contrast enhancement of adrenal tuberculosis could be quantitatively measured. As demonstrated by Ma et al[9], the difference in average density of the central zone of the enlarged adrenal glands between nonenhanced and enhanced CT scans is significantly less than that of peripheral zone (29 ± 2 HU vs 36 ± 11 HU).

Generally, the contrastenhanced CT and MRI features of adrenal tuberculosis can provide information for the adrenal tuberculosis resulting in PAI, and might be useful for indicating the clinical duration of adrenal tuberculosis. However, some radiological features of adrenal tuberculosis could be similar with those of

necrosis in the central area appear as peripheral rim enhancement on noncontrast CT[2]. The enlarged adrenals without necrosis tissues in central zone display homogeneous enhancement on contrastenhanced scans[9]. The radiologic features reflect the pathologic feature of central caseous necrosis surrounded by fibrous tissue and granulomatous inflammatory tissue[32,33,41,42].

If continuous antituberculosis therapy has been carried out, the adrenal lesions demonstrate homogeneous density (Figures 2DF) or calcification in the center on CT scans, and the specific center with hypointense or isointense on T2 weighed images would appear on MRI due to a large amount of fibrous tissue, cicatrix, or calcification[2,3537]. When the lesions are completely substituted with fibrous tissue or calcification, the glands would show hypointense on all MR images[2].


A B

C D

E F

Figure 2 A 52-year-old woman who has anorexia, daytime somnolence and sweating in last three months with primary adrenal insufficiency due to adrenal tuberculosis. The unenhanced (A) and contrast-enhanced (B) CT scans reveal the mass-like enlargement of bilateral adrenals, but its contours are preserved with multifocal peripheral enhancement on axial (B) and coronary (C) reformed images. Three months after antituberculous therapy, the axial (D and E) and coronary (F) images demonstrate the initially enlarged adrenal glands become small with homogeneous density in the center, and decrease of probability of the presence of peripheral rim enhancement. CT: Computed tomography.


adrenal fungal infections such as adrenal histoplasmosis. The diagnosis of adrenal tuberculosis should be considered in patients who has the CT and MRI features, and who has resided in an area where tuberculosis is not well controlled. Sometimes, biopsy is necessary for the diagnosis.

CONCLUSIONAdrenal tuberculosis can result in PAI. CT and MRI play important roles in the diagnosis of adrenal tuberculosis. Speed and availability of CT are of great importance to the diagnosis, and MRI can avoid the ionizing radiation

and perform multiparametric imaging and good spatial resolution. The radiological tools can well depict adrenal tuberculosis based on their pathologic nature and the duration of the illness, and the type of treatment. Understanding the imaging characteristics of adrenal tuberculosis is of great importance for correcting diagnosis and timely essential treatment of PAI secondary to adrenal tuberculosis.

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D

A B

C

Figure 3 A 44-year-old man who has hypoglycemia and low blood pressure with primary adrenal insufficiency due to adrenal tuberculosis. MRI scans reveal the mass-like enlargement of bilateral adrenal glands on axial T1- weighted image (A) and T2-weighted image (B), but its contours are preserved with peripheral enhancement on contrast-enhanced axial (C) and coronal (D) T1-weighted image. MRI: Magnetic resonance imaging.

Figure 4 A 51-year-old man with pigmentation of skin and blood electrolyte abnormalities due to primary adrenal insufficiency due to adrenal tuberculosis. The unenhanced (A) and contrast-enhanced (B) CT scans illustrate the enlargement of the left adrenal gland with peripheral enhancement. This patient underwent adrenal pathology biopsy, and photomicrograph (C) shows central caseous necrosis surrounded by granulomatous inflammatory cells (× 40). CT: Computed tomography.

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P- Reviewer: Chu JP, Garcia-Elorriaga G, Gumustas OG, Kumar J, Stanciu C

S- Editor: Qiu S L- Editor: A E- Editor: Jiao XK



Functional assessment of transplanted kidneys with magnetic resonance imaging

Yu-Ting Wang, Ying-Chun Li, Long-Lin Yin, Hong Pu, Jia-Yuan Chen

Yu-Ting Wang, Ying-Chun Li, Long-Lin Yin, Hong Pu, Jia-Yuan Chen, Department of Radiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610072, Sichuan Province, China

Author contributions: Wang YT and Chen JY developed the conception and designed the research; Wang YT, Li YC, Yin LL and Pu H performed the review of literature; Wang YT wrote the manuscript.

Supported by Scientific Research Subject of Health Department of Sichuan, China, No. 070045.

Conflict-of-interest statement: There is no conflict of interest associated with any of the authors contributed their efforts in this manuscript.


Correspondence to: Yu-Ting Wang, MD, Physician of Radiology, Department of Radiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, No. 32, Section 2, 1st Ring Road (West), Chengdu 610072, Sichuan Province, China. [email protected]: +86-28-87394280

Received: June 11, 2015Peer-review started: June 15 2015First decision: August 4, 2015Revised: August 17, 2015 Accepted: September 7, 2015Article in press: September 8, 2015Published online: October 28, 2015

AbstractKidney transplantation has emerged as the treatment of

choice for many patients with end-stage renal disease, which is a significant cause of morbidity and mortality. Given the shortage of clinically available donor kidneys and the significant incidence of allograft dysfunction, a noninvasive and accurate assessment of the allograft renal function is critical for postoperative management. Prompt diagnosis of graft dysfunction facilitates clini-cal intervention of kidneys with salvageable function. New advances in magnetic resonance imaging (MRI) technology have enabled the calculation of various renal parameters that were previously not feasible to measure noninvasively. Diffusion-weighted imaging provides information on renal diffusion and perfusion simultaneously, with quantification by the apparent diffusion coefficient, the decrease of which reflects renal function impairment. Diffusion-tensor imaging accounts for the directionality of molecular motion and measures fractional anisotropy of the kidneys. Blood oxygen level-dependent MR evaluates intrarenal oxygen bioavailability, generating the parameter of R2* (reflecting the concentration of deoxyhemoglobin). A decrease in R2* could happen during acute rejection. MR nephro-urography/renography demonstrates structural data depicting urinary tract obstructions and functional data regarding the glomerular filtration and blood flow. MR angiography details the transplant vasculature and is particularly suitable for detecting vascular complications, with good correlation with digital subtraction angiography. Other functional MRI technologies, such as arterial spin labeling and MR spectroscopy, are showing additional promise. This review highlights MRI as a comprehensive modality to diagnose a variety of etiologies of graft dysfunction, including prerenal (e.g. , renal vasculature), renal (intrinsic causes) and postrenal (e.g. , obstruction of the collecting system) etiologies.

Key words: Magnetic resonance imaging; Diffusion-weighted imaging; Diffusion-tensor imaging; Kidney transplantation; Dysfunction; Magnetic resonance renography; Blood oxygen level-dependent; Magnetic resonanc angiography; Functional evaluation

MINIREVIEWS







Core tip: Kidney transplantation has been widely used clinically, and early detection of graft dysfunction with noninvasive imaging is crucial for postoperative management. Conventional imaging mainly focuses on morphology and has limited utility in functional aspects. Magnetic resonance imaging (MRI) has excellent soft-tissue contrast, and new technologies, such as diffusion-weighted imaging, diffusion-tensor imaging, blood oxygen level-dependent MRI, MR nephro-urography/renography, and MR angiography, provide more functio-nal information and are therefore are well suited to graft evaluation. This review illustrates the utility of functional MRI as a comprehensive modality to diagnose a variety of etiologies of graft dysfunction.

Wang YT, Li YC, Yin LL, Pu H, Chen JY. Functional assessment of transplanted kidneys with magnetic resonance imaging. World J Radiol 2015; 7(10): 343-349 Available from: URL: http://www.wjgnet.com/1949-8470/full/v7/i10/343.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.343

BACKGROUNDRenal transplantation has been established as the preferred treatment for patients with end-stage renal diseases. It provides better a quality of life by sparing patients from lifelong dialysis and reduces morbidity and mortality. Early characterization and monitoring of dysfunction after renal transplantation are crucial to allow effective treatments and to improve the chance of a successful outcome[1]. Despite continuously improving surgical techniques and immunosuppressive therapies, surgical and medical complications can still arise. After renal transplantation, at least one episode of acute allograft dysfunction occurs in approximately 30%-40% of patients. These dysfunctions have a variety of causes, including prerenal (e.g., renal vasculature), renal (mostly intrinsic causes) and postrenal (e.g., obstruction of the transplant collecting system) etiologies[2,3].

The assessment of such large range of pathologies is difficult and relies heavily on invasive biopsies, with a risk of graft injury and loss[4]. Noninvasive imaging evaluation of transplanted kidneys has been widely used and offers anatomic evaluation of possible com-plications; however, medical complications, such as acute and chronic rejection, acute tubular necrosis (ATN), and drug-related toxicity, remain diagnostic challenges[5]. The utility of magnetic resonance imaging (MRI) in transplanted kidneys has been described for both anatomic and functional aspects, and it offers critical insights into the above-mentioned problems[6-8]. In addition to the conventional MR sequences, new technologies, such as diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI), blood oxygen

level-dependent (BOLD) imaging, nephro-urography, renography, and MR angiography (MRA), are being tested, and increasing amounts of clinical data are available. This article reviews the research progress of these technologies on the functional assessment of renal allograft and describes their specific clinical applications to diagnose various causes of graft dysfunction.

DWI AND DTIInitially developed for the diagnosis of acute stroke, DWI has recently gained increasing importance in imaging beyond the brain for functional assessment[9]. Any clinical MR unit can provide diffusion-weighted images by adding two equally large but opposite magnetic field gradients. Improved MR systems allows better magnetic field homogeneity, more effective fat suppression, fewer distortion artifacts and, probably most importantly, much stronger imaging gradients, therefore generating high-quality images with a su-fficient signal-to-noise ratio[5]. Compared to brain imaging, DWI in the lower abdomen is challenging due to motion-related artifacts. Optimization includes the reduction of echo times and geometric distortions, and nearly all examinations are performed by using echo planar imaging (EPI) sequences in the kidneys[10-12]. For quantitative image analysis, DWI yields a total “apparent diffusion coefficient” (ADCT) that provides information on diffusion and perfusion properties simultaneously if their contribution to total tissue diffusion can be separated. It is recommended that the ADCs of the medulla and cortex of the kidneys be analyzed separately if possible, due to their different intrinsic characteristics[5].

In the kidneys, diffusion properties may be aniso-tropic because the main structures, such as vessels and tubules, exhibit a radial orientation, but DWI does not account for the directionality of molecular motion. The fractional anisotropy (FA) of the kidneys can be assessed by DTI. The images can also be acquired with EPI sequence, and parametric ADC and FA maps can be calculated online during image postprocessing[13].

There currently are relatively limited data on the use of DWI in the assessment of transplanted kid-neys. Thoeny et al[10] investigated the DW imaging of transplanted kidneys in fifteen patients in stable condition and native kidneys in fifteen matched healthy volunteers. They measured ADCT, an ADC reflecting pure diffusion (ADCD) and the perfusion fraction (FP). Compared with normal kidneys, renal allograft exhibited a lack of corticomedullary difference in the diffusion parameters. The authors claimed it was probably due either to the denervation of transplanted kidneys or to the secondary effects of immunosuppressive drugs. They also measured the within-subject parameters of repeated MRI, and coefficients of variation indicated that ADC was highly reproducible. In the same study, several examples were shown that focal hyperintense areas (corresponding to low ADC) might suggest acute rejection (AR) in pathological examinations.

Wang YT et al . Functional MRI of transplanted kidneys


Eisenberger et al[14] presented similar results on the lack of corticomedullary difference of transplanted kidneys using DWI. Moreover, they compared renal allografts with stable function and those with AR or ATN soon after transplantation, using histology sections from the biopsies as the reference. The results showed that the ADCT values and, more remarkably, FP were reduced in transplanted kidneys with AR and ATN, while ADCD stayed relatively similar for all subjects. FP values strongly decreased to less than 12% in the cortex and medulla of renal transplants with AR and ATN. The estimated glomerular filtration rate (eGFR) was shown to be significantly correlated with the FP in the cortex and medulla, but not with ADCT or ADCD. Therefore, the authors proposed FP as the most accurate indicator for allograft function assessment soon after transplant.

More recently, Kaul et al[15] compared DWI of renal allograft on the 7th day post-transplantation and corresponding kidney biopsy results. The ADC values were found to be slightly lower in the medulla compared with the cortex in transplanted kidneys with normal function. They also reported a significant reduction of ADC values in both the cortex and the medulla in allografts with abnormal function. More remarkably, such a reduction was correlated with the degree of rejection on the biopsies. Furthermore, the increase in ADC values was observed during the recovery from rejection, suggesting the usefulness of DWI for therapy monitoring after rejection episodes.

Lanzman et al[13] conducted DTI in addition to DWI in patients with kidney transplants. They employed eGFR to differentiate allografts into good or moderate function and impaired function. In functionally impaired renal allografts, both FA and ADC of the renal medulla and cortex were significantly lower, and the corticomedullary difference in FA values was also lower. The FA of the medulla exhibited a high correlation with eGFR, while that of the cortex did not. In a more recent study con-ducted by Fan et al[16], similar results were reported, and the FA of the medulla was proposed as a valuable indicator of allograft function. These data indicated that the results of DTI were generally concordant with DWI, while DTI might offer additional information on the differences between the renal medulla and cortex caused by anisotropy.

BOLD MRIWith the ability to measure intrarenal oxygenation, BOLD MRI has been used in native kidneys and has shown differences in medullary oxygenation during pat-hological conditions such as renal artery occlusion, water diuresis, and pharmacologic stimulation with Lasix, acetazolamide, and nitric oxide[17,18]. Most published studies used a multiple gradient-recalled-echo sequence to perform BOLD MRI[10,19,20]. This technique generates the parameter of R2*, which is a measure of the rate of signal loss in a specific region and is related to the concentration of deoxyhemoglobin. Usually, R2* levels

are measured using the regions of interest (ROIs) tool. Experienced radiologists position certain numbers of ROIs in the cortical region and in the medullary region on the color R2* map.

Thoeny et al[10] compared BOLD images of the kidneys in patients with renal allografts and in healthy volunteers. Medullary R2* was observed to be sig-nificantly lower in the patients than in the volunteers. Moreover, coefficients of variation of repeated MRI showed that R2* was quite reproducible. This study investigated the correlation of parameters of DW imaging and BOLD imaging. In transplanted kidneys, R2* correlated negatively with ADCT and ADCD in the medulla.

Sadowski et al[19] also conducted BOLD MRI in patients who had received renal transplants. Twenty patients were included who had normal renal function, biopsy-proved ATN or AR. R2* values for the medulla were significantly lower in the AR group than the normal group and the ATN group. Using a certain threshold R2* value (18/s in this study), AR could be differentiated from normal function and ATN. R2* values for the cortex were higher in the ATN group than in the normal group and the AR group. More recently, Han et al[20] revealed similar results in a much larger patient group (110 patients). Sadowski et al[19] reported that the decreased R2* values in the medulla of kidneys with rejection could be due to changed hemodynamics and/or to reduced local oxygen consumption caused by decreased tubular function. These results established BOLD MRI as a promising tool to differentiate between AR and ATN.

MR NEPHRO-UROGRAPHY/RENOGRAPHYMR nephro-urography/renography assessment of the renal allograft combines structural and functional data within a single imaging examination. While T2W images provide excellent anatomic information, post-contrast T1W 3D gradient-echo images have the capacity to provide functional data in addition to tissue enhancement. New advances in the quick acquisition of dynamic, postcontrast, time-resolved images and delayed postcontrast excretion urographic images have introduced comprehensive MR nephro-urography and renography, enabling quantitative measurements of renal function, including individual kidney GFR and renal blood flow, in postprocessing. More recently, multicompartmental kinetic modeling was applied in the postprocessing of MR renography, generating separate parameters for the vascular and tubular compartments[21-24]. This model benefits from the use of the lowest possible concentration of gadolinium-chelate[3].

To assess intrinsic causes of renal dysfunction, such as AR and ATN, Yamamoto et al[24] performed quanti-tative low-dose 3D MR renography on sixty patients with transplanted kidneys. The GFR and the mean transit time (MTT) of the tracer were calculated using a multicompartment renal model. GFR and MTTK (MTT for the whole kidney) were significantly lower in the acute



MRA to assess the renal parenchyma and peritransplant regions as well as vascular abnormalities[1,28].

After conventional T1-weighted and T2-weighted sequences, an additional respiratory triggered 2D steady-state free precession (SSFP) sequence could be performed to visualize the vascular structure and generate reference images for planning the 3D contrast-enhanced MRA. A 3D gradient-echo sequence could then be initiated for angiography if contrast is used[1,29].

Table 1 displays the main findings of the studies investigating the use of MRA for the assessment of transplanted kidneys[1,28-34]. The primary strength of MRA is evaluating the stenosis of relevant arteries, and the results of these studies have shown a generally good correlation of MRA with digital subtraction angio-graphy (DSA), which is the golden standard for vascular abnormalities. Other vascular complications, such as vein stenosis and arteriovenous fistulas, can also be detected; several studies have also reported the use of MRA to detect renal parenchymal infarctions and perfusion defects[28,30].

There has been an ongoing discussion about the use of contrast agents. Early results have shown that timeofflight MRA had inferior diagnostic effectiveness compared to contrast-enhanced MRA[28]. In addition to conventional gadolinium chelate-based contrast agents, new contrasts claiming to be nonnephrotoxic, such as ferumoxytol, have been used in clinical trials. The initial findings of Bashir et al[33] in renal transplant MRA using ferumoxytol have demonstrated excellent depiction of the transplant vasculature.

Recently, unenhanced MRA with advanced tech-niques, such as SSFP alone and spatial labeling with multiple inversion pulses, has made substantial progress and has been reported to be of comparable image quality and diagnostic accuracy with contrast-enhanced

dysfunction group than the normal function group. More specifically, the MTTA/K (fractional MTT of the tracer for the vascular compartment) was significantly higher in the AR group than in the normal function group or the ATN group. The MTTT/K (fractional MTT of the tracer for the tubular compartment) was significantly higher in the ATN group than in the normal function group or the AR group. The authors therefore claimed that this technique might help discriminate between AR and ATN. Researchers have also explored the use of other quantitative parameters, such as the medullary nephronal washout rate and the cortical arterial blood volume, but the results are still preliminary[25].

To assess the postrenal etiology of renal allograft dysfunction, MR nephro-urography/renography offers functional information in addition to the exceptional soft-tissue contrast provided by standard MR images. Kalb et al[3] has demonstrated how MR nephro-uro-graphy can guide clinical management the with above-mentioned advantages. In addition to identifying anatomic variations, obstruction of transplant ureters, and fibrosis at certain anastomotic sites secondary to chronic ischemia, MR nephro-urography can enable precise measurement of GFR, thereby reflecting graft function.

MRA WITH OR WITHOUT CONTRASTVascular complications, such as artery stenosis, are relatively uncommon and are reported to occur in 5%-15% of transplanted kidneys, but they are a major cause of transplant loss, which usually necessitates resuming dialysis[26,27]. Early and accurate diagnosis becomes critical because such complications are often correctable, and timely intervention can help salvage the graft kidney. Several studies have revealed the ability of


Ref. Year No. of Pt Contrast Criteria for artery stenosis MRA findings Reference and accuracy

Huber et al[28] 2001 41 Uncleara > 0% as clinically significant 23 significant artery stenosis, 2 vein complications, 4 perfusion defects of

the parenchyma

DSA; Se: 100%; Sp: 93%-97%

Gufler et al[33] 2008 63 Gd-DTPA < 50%: mild; Artery stenosis: 29 mild, 3 moderate, and 1 severe

DSA for severe stenosis, one overestimati-on50%-70%:moderate;

> 70%:severeLanzman et al[34] 2009 20 None (SSFP) ≥ 50% as clinically significant 6 significant artery stenosis DSA; Se: 100%; Sp: 88%Liu et al[30] 2009 13 None (SSFP) ≥ 50% as clinically significant 1 significant artery stenosis Stenosis confirmed by DSA Ismaeel et al[31] 2011 30 Uncleara

≥ 50% as clinically significant 15 significant artery stenosis DSA; Se: 93.7%; Sp: 80%Bashir et al[32] 2013 16 Ferumoxytol Unclear 2 moderate to severe stenosis, 1

occlusionStenosis and occlusion

confirmed by DSA Hwang et al[1] 2013 144 Gadobutrol < 50%: mild; Artery stenosis: 10 mild, 5 moderate,

and 8 severe; 17 renalSevere stenosis confirmed

by DSA50%-70%: moderate; parenchymal infarctions

> 70%: severeTang et al[29] 2014 75 None (SLEEK) ≥ 50% as clinically significant 14 artery stenosis (10 significant), other

complications such as arteriovenous fistulas and pseudoaneurysms

Significant stenosis: DSA; positive predictive value:

91%

Table 1 Main findings of recent studies exploring the use of magnetic resonance angiography

aWith contrast, but unclear about the specific name. Pt: Patients; SSFP: Steady-state free precession; SLEEK: Spatial labeling with multiple inversion pulses; DSA: Digital subtraction angiography; Se: Sensitivity; Sp: Specificity; MRA: Magnetic resonance angiography.


MRA[30,31]. However, the image quality of different artery segments might vary, as the image quality of the branches was observed to be inferior to that of the main arteries[34].

OTHER FUNCTIONAL MRI TECHNIQUESArterial spin labeling (ASL) MRI was developed to measure tissue perfusion data and has been used extensively in the brain. Lanzman et al[35] conducted ASL MRI in 20 renal allograft recipients, divided into a good function group and an acute deterioration of renal function group. Quantitative measurement showed that cortical perfusion values were significantly reduced in transplanted kidneys with impaired function[35]. Another study evaluated the reproducibility of ASL MRI in both native and transplanted kidneys. Intraclass correlation and coefficients of variation indicated that this technique was reproducible in the cortexes of native and transplanted kidneys, but that it demonstrated moderate to poor reproducibility for intravisit and intervisit measures in the medulla[36].

Studies have reported that chronic allograft dysfun-ction is accompanied by a decrease in the β-ATP/Pi ratio, a marker of kidney high-energy phosphate metabolism, as assessed by 31P- magnetic resonance spectroscopy (MRS), and that a relatively highβ-ATP/Pi ratio (> 1.20 AU in one study) might indicate a good graft survival (probability > 3 years). Early improvement in the β-ATP/Pi ratio (within 6 mo) in renal transplant patients receiving short-term low-dose valsartan treatment can be detected by 31P-MRS[37].

Magnetic resonance elastography (MRE) generates a quantitative measurement of tissue stiffness and has been widely used in the liver to assess the degree of fibrosis. Lee et al[38] performed MRE on 11 renal transplant patients and compared calculated the tissue stiffness value with histologic results. The mean stiffness value of patients with moderate interstitial fibrosis was higher than that of patients with mild or no interstitial fibrosis, but not significantly so. The authors suggested that multiple factors can influence renal stiffness[38].

COMPARISON OF OTHER MODALITIES AND CLINICAL INDICATIONSIn evaluating transplanted kidneys, several imaging modalities are available for clinicians. The dysfunction of renal grafts is often clinically asymptomatic and pre-sents only with an isolated increase in serum creatinine. To detect intrinsic etiologies, such as ATN or AR, color Doppler ultrasonography (US) is widely used because of its convenience and lack of radiation or toxic dye. However, it is user-dependent and its findings are often nonspecific for a final diagnosis or confirmation of normal function. Nuclear medicine (NM) imaging can be used to establish the flow, but its results can also be nonspecific to identify etiologies of dysfunction,

and it is time-consuming and not readily available[8]. Functional MR technologies, such as DWI and DTI, could be recommend when patients have clinically suspicious intrinsic etiologies of graft dysfunction and negative or obscure results from US or NM imaging. Furthermore, these technologies have potential to monitor graft function during therapies. Quantitative measurements by BOLD MRI or 3D MR renography (especially when a multicompartment renal model is available) are worth considering to further differentiate between AR and ATN.

US is usually considered the firstline test to assess urologic obstructions, but the relatively poor anatomic detail it allows could lead to failure to identify the causes of the obstruction[3,8]. Computed tomography (CT) can be used to detect nephrolithiasis-related obstructions, but it uses iodinated radiation and carries the risk of contrast nephropathy. MR nephro-urography can be recommended in such cases. With the exceptional soft-tissue contrast, MR nephro-urography may reveal causes such as anatomic variations and fibrosis at certain anastomotic sites while generating the precise value of GFR at the same time.

To evaluate vascular complications, US is generally used first, but it may be limited by the interposition of bowel gas between the transducer and the graft, and by issues of angulation and tortuosity caused by the irregular curvilinear anatomy of transplanted renal arteries. In addition, US cannot accurately vis-ualize allograft artery stenosis in patients with high peak systolic velocities at the anastomosis[1,8]. DSA is confirmatory and has the capacity of simultaneous interventions, but it is invasive and expensive. Computed tomographic angiography is valuable for evaluating graft vessels, but again, it uses iodinated contrast agents and exposes the patient to ionizing radiation. Gadolinium chelatebased contrast agents used in enhanced MRI are believed to be generally safer, and MRA without contrast with improved image quality and diagnostic accuracy has been proposed[30,31,34]. Abun-dant evidence has shown the good correlation of MRA with DSA. Usually, patients with suspicion of transplant-related renal vascular complications, such as refractory hypertension and/or worsening graft function, elevated serum creatinine levels and nondiagnostic US findings are examined with MRA, which can assess renal parenchyma blood supply and the peritransplant region conditions in addition to the vascular abnormality.

MRI has limitations in clinical practices as well. It is less frequently available because, unlike US, the equipment is not portable, the cost is relatively high, and it requires specialized personnel who may not be available 24 h/d. Moreover, it carries the risk of nephrogenic systemic fibrosis in patients with a GFR lower than 30 mL/min per 1.73 m2 in gadolinium-based studies[8]. As with all medical procedures, a rational judgment must be applied to weigh the potential benefits against the risks.



CONCLUSIONTo summarize, renal transplantation has been widely used clinically, and MRI is a noninvasive technique well suited for the assessment of renal allografts. Given the functional information provided by new technolo-gies, MRI should be considered as a promising and powerful tool in the diagnostic workup for a variety of renal pathologic conditions, and it has the potential to significantly influence the postoperative management of kidney transplant patients. To further improve its diagnostic accuracy, a more comprehensive un-derstanding of MRI, as well as knowledge of clinical situations, is recommended. The use of reproducible and representative quantitative parameters could be further explored, and clinical trials with larger sample sizes and solid references could offer critical clues.

ACKNOWLEDGMENTSThe authors thank Dr. Jonathan Fullner for editing part of the manuscript.

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S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK



Relevant incidental findings at abdominal multi-detector contrast-enhanced computed tomography: A collateral screening?

Luca Maria Sconfienza, Giovanni Mauri, Claudia Muzzupappa, Alessandro Poloni, Michele Bandirali, Anastassia Esseridou, Stefania Tritella, Francesco Secchi, Giovanni Di Leo, Francesco Sardanelli

Luca Maria Sconfienza, Giovanni Mauri, Michele Bandirali, Anastassia Esseridou, Stefania Tritella, Francesco Secchi, Giovanni Di Leo, Francesco Sardanelli, Servizio di Radiologia, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Milano, Italy

Luca Maria Sconfienza, Francesco Secchi, Francesco Sardanelli, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, 20097 San Donato Milanese, Milano, Italy

Claudia Muzzupappa, Alessandro Poloni, Scuola di Specializzazione in Radiodiagnostica, Università degli Studi di Milano, 20122 Milano, Italy

Author contributions: Sconfienza LM, Mauri G, Di Leo G and Sardanelli F contributed to research pianification; Mauri G, Di Leo G and Sardanelli F contributed to statistical analysis; all authors contributed to data analysis, manuscript drafting and final approval.

Institutional review board statement: Institutional Review Board approval of IRCCS Ospedale San Raffaele, Milano, Italy was obtained.

Informed consent statement: Patients’ informed consent was waived.

Conflict-of-interest statement: Authors have no conflict of interest to disclose related to the present paper.

Data sharing statement: Dataset is available from the corresponding author according to what is foreseen by the IRB.

Open-Access: This article is an openaccess article which was selected by an inhouse editor and fully peerreviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and

the use is noncommercial. See: http://creativecommons.org/licenses/bync/4.0/

Correspondence to: Luca Maria Sconfienza, MD, PhD, Servizio di Radiologia, IRCCS Policlinico San Donato, Piazza Malan 1, 20097 San Donato Milanese, Milano, Italy. [email protected]: +390252774468Fax: +390252774925

Received: May 16, 2015 Peer-review started: May 20, 2015 First decision: July 10, 2015Revised: July 31, 2015 Accepted: August 20, 2015Article in press: August 21, 2015Published online: October 28, 2015

AbstractAIM: To investigate the prevalence of relevant incidental findings (RIFs) detected during routine abdominal contrast-enhanced computed tomography (CeCT).

METHODS: We retrospectively evaluated the reports of a consecutive series of abdominal CeCT studies performed between January and May 2013. For each report, patients’ age and sex, admission as inpatient or outpatient, clinical suspicion as indicated by the requesting physician, availability of a previous abdominal examination, and name of the reporting radiologist were recorded. Based on the clinical suspicion, the presence and features of any RIFs (if needing additional workup) was noted.

RESULTS: One thousand forty abdominal CeCT were performed in 949 patients (528 males, mean age 66 ±






Retrospective Cohort Study

ORIGINAL ARTICLE

14 years). No significant difference was found between inpatients and outpatients age and sex distribution (P > 0.472). RIFs were found in 195/1040 (18.8%) CeCT [inpatients = 108/470 (23.0%); outpatients = 87/570 (15.2%); P = 0.002]. RIFs were found in 30/440 (6.8%) CeCT with a previous exam and in 165/600 (27.5%) without a previous exam (P < 0.001). Radiologists’ distribution between inpatients or outpatients was significantly different (P < 0.001). RIFs prevalence increased with aging, except for a peak in 40-49 year group. Most involved organs were kidneys, gallbladder, and lungs.

CONCLUSION: A RIF is detected in 1/5 patients under-going abdominal CeCT. Risk of overdiagnosis should be taken into account.

Key words: Contrast-enhanced computed tomography; Abdomen; Incidental findings; Screening; Overdiagnosis


Core tip: A relevant incidental finding (IF) is detec-ted in one out of five patients undergoing abdominal contrast-enhanced computed tomography. Thus, in clinical practice, we daily perform unconscious collateral screening for a number of abdominal diseases. Notably, a problem still exists about how to deal with these findings, as their detection can be stressful and potentially harmful for patients, also contribute to increase in health care costs. On the one hand we have the risk of overdiagnosis, on the other hand there is a risk of legal issues for not having reported and suggested further work-up for these IFs.

Sconfienza LM, Mauri G, Muzzupappa C, Poloni A, Bandirali M, Esseridou A, Tritella S, Secchi F, Di Leo G, Sardanelli F. Relevant incidental findings at abdominal multi-detector contrast-enhanced computed tomography: A collateral screening? World J Radiol 2015; 7(10): 350-356 Available from: URL: http://www.wjgnet.com/19498470/full/v7/i10/350.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.350

INTRODUCTIONContrast-enhanced computed tomography (CeCT) has gained a crucial role in medical practice[1]. With the increase of number and quality of CeCT examinations, a concurrent increase of unexpected (incidental) fin-dings unrelated to clinical suspicion has occurred[2]. Most of these incidental findings (IFs) are immediately recognized as benign or as anatomical variants and have no clinical relevance, but in a number of IFs additional workup is needed to reach a final diagnosis. This in turn generates anxiety for patients and additional costs for the healthcare systems[3].

The discovery of an IF has been cited among the

causes of increased use of cross-sectional imaging and ionizing radiation exposure for medical reasons, being theoretically even detrimental for the patient[1]. Balancing the benefit of an early detection of a disease with the risk of overdiagnosis is crucial from a societal viewpoint when a screening program is planned[4]. Although some attempts to standardise the manage-ment of IFs have been made, in the clinical practice their management still vary widely between physicians and countries[5].

Several studies have been devoted to assess the prevalence of IFs and their relevance[6-12]. They have generally been performed to evaluate collateral fin-dings detected during an imaging study dedicated to a single anatomical structure (e.g., IFs detected during CT colonography or cardiac CT/MRI, breast MRI, etc.)[6-11] or performed in a specific clinical setting (e.g., IFs discovered during emergency abdominal CT)[12]. Conversely, no data are available about relevant IFs that are occasionally detected in a series of consecutive patients undergoing abdominal CeCT.

The purpose of our work was to investigate the prevalence of relevant IFs detected during abdominal CeCT in the daily routine at our institution.

MATERIALS AND METHODSInstitutional Review Board approval of IRCCS Ospedale San Raffaele, Milano, Italy was obtained and patients’ informed consent was waived. Our report is concerned with a retrospective evaluation of the reports of a consecutive series of abdominal CeCT performed at our institution between January and May 2014, including inpatients, outpatients, and patients coming from the emergency department. The last ones were considered as outpatients. CeCT examinations were performed using either a 16- or 64-slice CT systems (SOMATOM Emotion and Sensation, respectively; Siemens Medical, Erlangen, Germany) with oral administration of variable amount of diluted water-soluble iodinated contrast agent (Gastrografin, Bayer-Schering, Germany) and intravenous injection of iodinated contrast agent (Iomeron 350, Bracco, Milano, Italy) using different acquisition protocol according to the clinical suspicion. Electronic reports were retrieved from our radiology information system (RIS) (PolaRIS, El.Co., Cairo Mont-enotte, Savona, Italy) and were reviewed in consensus by two radiology residents (CM and MB) with three years’ experience in CeCT. For each report, they recorded patients’ age and sex, his/her admission as inpatient or outpatient, the clinical suspicion as indicated by the requesting physician, and the name of the radiologist who signed the report. Based on the clinical suspicion, the report was searched to detect the presence of relevant IFs. IF was defined as “an incidentally discovered mass or lesion detected by abdominal CeCT performed for an unrelated reason”[5]. IFs were considered as relevant if additional workup (other imaging tests, clinical evaluation, or follow-up) was suggested by the reporting

Sconfienza LM et al . Relevant incidental findings at abdominal multi-detector CeCT


radiologist. If no specific note was included in the report, the two reviewers assessed in consensus the needing of additional workup. In case of disagreement, a staff radiologist with 10 years of experience in CeCT (LMS) addressed the issue.

For all patients, reviewers noted the presence of previous cross-sectional imaging exams (ultrasound, CT, or magnetic resonance imaging) performed within one year. If this information was already included in the report, patients were classified as provided with a previous examination. Thus, reviewers rated any newly reported IF as not already known. If the report did not include any information, previous exams were searched for in our RIS. Finally, if none of the two abo-vementioned criteria were applicable, patients were considered to be lacking of previous exams. For patients who underwent more than one abdominal CeCT in the considered period, the first exam was treated according to the abovementioned criteria, while the second and/or the third following exam was considered to have an available previous exam.

Relevant IFs were also stratified according to 10-year age groups and classified according to the organ involved.

Data and statistical analysisStatistical analysis was performed by one of the authors (GDL) who has advanced statistical expertise. Data regarding the present paper may be shared upon request prior further Institutional Review Board Approval.

Age distribution between inpatients and outpatients subgroups was compared using the U Mann-Whitney test. Sex distribution between inpatients and outpatients, as well as relevant IFs distribution in our series was compared within different subgroups (inpatients, out-patients, patients with or without a previous exam) using the Chi-square test. Odds ratios were also calculated. All calculations were performed using SPSS Statistics v. 19 (SPSS, Chicago, IL, United States) and Excel (Microsoft Excel® 2010, Redmond, WA, United States). A P-value less than 0.05 was considered as significant.

RESULTSIn the considered period, 1040 abdominal CeCT were performed in 949 patients (528 males, 421 females,

mean age ± standard deviation 66 ± 14 years); 75 patients underwent two CeCT examinations and eight patients underwent three CeCT examinations.

Four hundred seventy out of 1040 (45.2%) CeCT examinations were performed in 401 inpatients (228 males, 173 females; mean age 67 ± 15 years) and 570/1040 (54.8%) in 548 outpatients (300 males, 248 females; mean age 65 ± 12 years). Age and sex distribution was not significantly different between inpatients and outpatients (P = 0.472 and P = 0.717, respectively).

Overall, relevant IFs were found in 195/1040 (18.8%) CeCT, one IF per exam: 108/470 (23.0%) in inpatients and 87/570 (15.2%) in outpatients, the diffe-rence being statistically significant (P = 0.002).

A previous exam was available for 440/1040 (42.3%) CeCT examinations while it was not available for the remaining 600/1040 (57.7%). Relevant IFs were found in 30/440 (6.8%) CeCT with a previous exam and in 165/600 (27.5%) with no previous exam (P < 0.001). Subgroup analyses between inpatients and outpatients, with or without a previous exam are reported in Tables 1 and 2. No statistical difference was found regarding the number of patients with or without previous exams subdivided into inpatients and outpatients.

Exams were reported by nine different radiologists with three to 20 years experience in abdominal CeCT. The distribution of radiologists who reported CeCT exams of inpatients or outpatients was significantly different (P < 0.001). Full data are reported in Table 3.

Distribution of relevant IFs stratified according to 10-year age groups (total, inpatients, and outpatients) is shown in Table 4 and graphically represented in Figure 1.

Distribution of relevant IFs among involved organs is shown in Table 5. A list of the relevant Ifs is reported in Table 6.

DISCUSSIONThis study was performed to evaluate the prevalence of relevant IFs in a consecutive series of patients who underwent abdominal CeCT at our institution. Our study shows that relevant IFs are commonly encountered, being detected in about one fifth of patients undergoing abdominal CeCT.

Prevalence of IFs has been reported in literature


Previous exam P Odds ratio

Yes No (no/yes)Inpatients 14/187 (7.5) 94/283 (33.2) < 0.001 4.7Outpatients 16/253 (6.3) 71/217 (22.4) < 0.001 3.7p 0.632 0.003

Table 1 Percentage of relevant incidental findings among inpatients and outpatients, with or without a previous exam n (%)

P-values were calculated using the χ 2 test.

Previous exam Yes/no

Yes NoInpatients 187/1040 (18.0) 283/1040 (27.2) 0.66Outpatients 253/1040 (24.3) 317/1040 (30.5) 0.80Inpatients/outpatients 0.74 0.89 P = 0.152

Table 2 Number of inpatients and outpatients with or without a previous exam n (%)

P-value was calculated using the χ 2 test.


them were mentioned in the report. O’Connor et al[10] reported a 14% IFs prevalence in kidneys, while IFs prevalence in adrenal glands was reported to range between 3% and 7%[16]. Some authors investigated IFs prevalence in a specific setting, such as patients who underwent abdominal CT in emergency. In this particular context, IFs prevalence has been reported between 15% and 35%[12]. A recent literature review on 44 original studies on all imaging diagnostic modalities published between 1986 and 2007 reported a IFs mean prevalence of 23.6%[2]. To our knowledge, no previous report investigated the overall prevalence of relevant IFs in a consecutive series of routine abdominal CeCT.

In our series, we found a significantly higher amount of relevant IFs in inpatients compared to outpatients. This result could be explained by the fact that CT exams performed in inpatients are generally requested with a focused clinical question (e.g., staging in a patient with colon cancer). As findings are considered as incidental solely when not related to the clinical suspicion, the narrower the clinical suspicion the higher the possibility to detect an unrelated finding[2]. Conversely, clinical

to vary from 3% to 58%[6-12], depending on the study population, the organ or system involved, and on criteria used to classify IFs. Several papers are focused on the rate of IFs detected during CT exams aimed to the evaluation of a single organ. For example, extracolonic IFs are reported to be detected in up to 23% of patients undergoing CT colonography[6,8] and this is nowadays considered one of the major issues regarding colon cancer screening with this technique. Dewey et al[13] reported a 5% prevalence of relevant extra-cardiac IFs and a 10% prevalence of non-relevant IFs during coronary CT angiography in a cohort of 108 patients. However, Gil et al[14] reported extra-cardiac IFs in 56% of their series, regardless to their severity. In the study of Law et al[15], 56 out of 295 patients (19%) had extra-coronary IFs requiring clinical or radiological follow up. Other studies deal with IFs prevalence in a single organ. Rinaldi et al[9] re-assessed the images of a series of abdominal CT exams to evaluate prevalence, reporting rates, and clinical implications of incidentally-discovered pulmonary nodules. In this retrospective case review, 39.1% of patients had lung nodules but only 8.4% of


Radiologist Overall Inpatients Outpatients

Reports Relevant IFs Reports Relevant IFs Reports Relevant IFsA 69/1040 (6.6) 11/69 (16.0) 43/470 (9.1) 8/43 (18.6) 26/570 (4.6) 3/26 (11.5)B 59/1040 (5.7) 11/59 (18.6) 21/470 (4.4) 3/21 (14.3) 38/570 (6.6) 8/38 (21.1)C 164/1040 (15.8) 23/164 (14.0) 75/470 (16.0) 12/75 (16.0) 89/570 (15.6) 11/89 (12.4)D 353/1040 (33.9) 81/353 (22.9) 145/470 (30.9) 41/145 (28.2) 208/570 (36.4) 40/208 (19.2)E 160/1040 (15.4) 21/160 (13.1) 48/470 (10.2) 9/48 (18.7) 112/570 (19.6) 12/112 (10.7)F 102/1040 (9.8) 12/102 (11.8) 70/470 (14.9) 10/70 (14.3) 32/570 (5.6) 2/32 (6.2)G 8/1040 (0.8) 3/8 (37.5) 5/470 (1.1) 2/5 (40.0) 3/570 (0.5) 1/3 (33.3)H 28/1040 (2.7) 8/28 (28.6) 11/470 (2.3) 4/11 (36.4) 17/570 (3.0) 4/17 (23.5)I 97/1040 (9.3) 25/97 (25.8) 52/470 (11.1) 19/52 (36.5) 45/570 (7.9) 6/45 (13.3)Total 1040/1040 (100.0) 195/1040 (18.8) 470/470 (100.0) 108/470 (23.0) 570/570 (100.0) 87/570 (15.3)

Table 3 Overall number of reports and relevant incidental findings per radiologist n (%)

Comparison between relevant incidental finding rate in inpatients or in outpatients was calculated using the χ 2 test and resulted significantly different (P < 0.001). IFs: Incidental findings.

Figure 1 Relevant incidental findings stratified according to 10-year age groups subdivided between inpatients, outpatients and overall.

10-19

70

60

50

40

30

20

10

020-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99

Total InpatientsOutpatients

perc

enta

ge o

f re

leve

nt in

clde

ntal

find

ings


suspicion reported in outpatients’ requests is usually more generic (e.g., abdominal pain), allowing for an easier correlation to a wide range of IFs, although this is not necessarily the rule. In our study, patients from emergency department were included in the outpatients group because they are often sent with a generic clinical suspicion, based on ill-defined clinical data and symptoms.

In our series, the only independent predictor of a relevant IF was the availability of a previous exam. In patients who had not performed a previous exam, the odds ratio calculation demonstrated a probability of detecting a relevant IF about five times greater than in those who had a previous exam available. This was expected, as IFs that had been already detected in previous exam have been currently considered as already known and thus excluded from our analysis.

We found significant difference in the distribution of radiologists who reported CeCT exams performed in inpatients or in outpatients. This data is partially due to statistical analysis of a large number of radiologists and a relatively small number of exams per each reader.

However, this could somewhat represent an additional explanation of the difference of relevant IFs prevalence


Age Overall Inpatients Outpatients

CeCT Relevant IFs CeCT Relevant IFs CeCT Relevant IFs10-19 6/1040 (0.6) 0/6 (0.0) 3/470 (0.6) 0/3 (0.0) 3/570 (0.5) 0/3 (0.0)20-29 17/1040 (1.7) 2/17 (11.8) 8/470 (1.7) 2/8 (25.0) 9/570 (1.6) 0/9 (0.0)30-39 40/1040 (3.8) 5/40 (12.5) 8/470 (1.7) 1/8 (12.5) 32/570 (5.6) 4/32 (12.5)40-49 88/1040 (8.5) 27/88 (30.6) 34/470 (7.2) 10/34 (29.4) 54/570 (9.4) 17/54 (31.5)50-59 130/1040 (12.5) 20/130 (15.4) 55/470 (11.7) 11/55 (20.0) 75/570 (13.6) 9/75 (12.0)60-69 260/1040 (25.0) 40/260 (15.4) 112/470 (23.8) 20/112 (17.8) 148/570 (26.0) 20/148 (13.5)70-79 361/1040 (34.7) 73/361 (20.2) 173/470 (36.8) 42/173 (24.2) 188/570 (33.0) 31/188 (16.5)80-89 129/1040 (12.4) 25/129 (19.4) 72/470 (15.3) 19/72 (26.4) 57/570 (10.0) 6/57 (10.5)90-99 9/1040 (0.8) 3/9 (33.3) 5/470 (1.1) 3/5 (60.0) 4/570 (0.7) 0/4 (0.0)Tot 1040/1040 (100) 195/1040 (18.8) 470/470 (100) 108/470 (23.0) 570/570 (100) 87/570 (15.2)

Table 4 Relevant incidental findings stratified according to 10-year age groups subdivided between inpatients, outpatients, and overall n (%)

CeCT: Contrast-enhanced computed tomography; IFs: Incidental findings.

Anatomical site Relevant IFs

Kidney 28/195 (14.4)Gallbladder 27/195 (13.85)Lung 24/195 (12.3)Uterus 20/195 (10.3)Adrenal gland 19/195 (9.7)Vessels 19/195 (9.7)Musculoskeletal 12/195 (6.2)Ovary 12/195 (6.2)Liver 7/195 (3.6)Spleen 6/195 (3.1)Prostate 6/195 (3.1)Bowel 5/195 (2.6)Bladder 4/195 (2.1)Pancreas 3/195 (1.5)Testicles 3/195 (1.5)

Table 5 Distribution of relevant incidental findings among involved organs n (%)

IFs: Incidental findings.

IF n %

Cholelithiasis 27 (2.6%)Uterine lesion 20 (1.9%)Adrenal mass 19 (1.8%)Non-simple renal cyst 15 (1.4%)Lung nodule 13 (1.3%)Adnexal mass 12 (1.2%)Kidney stones 10 (1.0%)Pleuric effusion 8 (0.8%)Focal liver lesion 6 (0.6%)Enlarged prostate 6 (0.6%)Focal splenic lesion 5 (0.5%)Abdominal aortic aneurysm 4 (0.4%)Bladder wall thickening 4 (0.4%)Aortic ectasia 4 (0.4%)Inguinal hernia 4 (0.4%)Focal pancreatic lesion 3 (0.3%)Focal renal lesion 3 (0.3%)Atheromasic aorta 3 (0.3%)Iliac aneurysm 3 (0.3%)Focal lesion of bones 3 (0.3%)Lung consolidation 2 (0.2%)Focal muscolar lesion 2 (0.2%)Appendicular enlargement 2 (0.2%)Hydrocele testis 2 (0.2%)Splenic artery aneurysm 1 (0.1%)Mesenteric artery aneurysm 1 (0.1%)Vertebral fracture 1 (0.1%)Diverticulitis 1 (0.1%)Ectasic portal vein 1 (0.1%)Endoleak 1 (0.1%)Emphysema 1 (0.1%)Spinal disc herniation 1 (0.1%)Colonic cancer 1 (0.1%)Stasis liver 1 (0.1%)Incisional hernia 1 (0.1%)Femoral artery occlusion 1 (0.1%)Splenomegaly 1 (0.1%)Subocclusion 1 (0.1%)Varicocele 1 (0.1%)Total 195 (18.7%)

Table 6 Relevant incidental findings in 1040 contrast enhanced computer tomography examinations

IF: Incidental finding.


between inpatients and outpatients.Considering age group stratification (see Table 4),

we found that relevant IFs increase with aging, as ex-pected[17]. An exception is represented by the 40-to-49 year group, in which relevant IFs prevalence was about one third. Patients included in such a group were lacking of a previous exam in 70% of cases, compared to the overall value of 57.7%. As the absence of a previous exam increase the possibility of relevant IFs detection, this data can somewhat explain the unusual prevalence peak in that age group.

Regarding the classification of relevant IFs according to the anatomical site, we note that the most involved organs were kidneys, gallbladder, and lungs. For renal lesions, there is no validated criteria - apart from follow-up - to differentiate solid benign from malignant lesions[18]. This could partially explain the high incidence of relevant IFs, as for these lesions additional workup is frequently recommended. Regarding gallbladder, 10%-15% of occidental subjects will develop galls-tones in their life. People with asymptomatic gallst-ones are likely to develop related problems in 1%-4% of cases, younger people being more at risk than elderly[19]. Although prophylactic cholecistectomy is usually unnecessary, this procedure can be justified in young subjects that are more prone to develop acute pancreatitis related to small stones[20]. This partially explains the high number of relevant IFs reported in our series, as additional workup (ultrasound follow-up or surgical evaluation) is usually suggested in these cases. In our series, we found 2.5% IFs related to lungs, considered as relevant in respect to previously published criteria[21]. In a previous paper, Rinaldi et al[9] reported an overall incidence of 39.1% of lung nodules visible on abdominal CeCT images, only 8.4% of them being described in radiologists’ report. However, our values are not directly comparable to theirs, as we included only reported incidentally discovered lung nodules deserving additional workup.

Early diagnosis and detection of asymptomatic diseases have well known advantages, being also at the basis of screening programs. However, additional workup of relevant IFs can be responsible of tests and procedure that are often expensive - both for patients and healthcare systems - stressful, and sometimes potentially harmful for patients (e.g., invasive pro-cedures or ionizing radiations exposure). Also, it can happen that IFs are so slow-progressing that will never cause symptoms or death. When this happens, the diagnosis might have been correct but is clinically irrelevant. This important concept is also known as over-diagnosis and it is a risk that should be always taken into account when dealing with screening tools and early diagnosis in general[4].

Our study has some limitations. First, it was con-ducted at a single institution, so results may be not directly transferable to general population. Then, the retrospective nature of the study that was aimed solely to review radiological reports. Thus, our action

was limited to analyze findings that were included in those reports. Also, our results may be somewhat underestimated. Moreover, being able to access previous exams only when provided by patients themselves or when performed at our institution have surely affected the data of patients considered as lacking of a previous exam. Finally, we do not know whether additional work-up was really performed. Thus we could not evaluate the real impact of IFs on the healthcare system.

Summarizing, a relevant IF is detected in one out of five patients undergoing abdominal CeCT. Thus, in clinical practice, we daily perform unconscious collateral screening for a number of abdominal diseases. Not-ably, a problem still exists about how to deal with these findings, as their detection can be stressful and potentially harmful for patients, also contributing to raise health care costs. On the one hand we have the risk of overdiagnosis, on the other hand the risk of legal issues for not having reported and suggested further work-up for these IFs[22].

COMMENTSBackgroundIncidental findings (IFs) during contrast-enhanced computed tomography (CeCT) are increasingly being detected. This generates anxiety for patients and additional costs for the healthcare systems.

Research frontiersThe study is concerned with the evaluation of IFs during CeCT of the abdomen.

Innovations and breakthroughsA relevant IF is detected in one out of five patients undergoing abdominal CeCT. Thus, in clinical practice, the authors daily perform unconscious collateral screening for a number of abdominal diseases.

ApplicationsA problem still exists about how to deal with these findings, as their detection can be stressful and potentially harmful for patients, also contribute to increase in health care costs. On the one hand we have the risk of overdiagnosis, on the other hand there is a risk of legal issues for not having reported and suggested further work-up for these IFs.

TerminologyAbdominal CE-CT: CeCT of the abdomen, a panoramic examination of the abdomen used to evaluate a wide range of pathologic conditions. IF: An incidentally discovered mass or lesion detected by abdominal CeCT performed for an unrelated reason.

Peer-reviewThe manuscript is well written.

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P- Reviewer: Chu JP, Kumar J S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK



Delayed diagnosis of isolated alar ligament rupture: A case report

Robin A Kaufmann, Ingo Marzi, Thomas J Vogl

Robin A Kaufmann, Thomas J Vogl, Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany

Ingo Marzi, Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany

Author contributions: Kaufmann RA was mainly responsible for writing and researching the paper; Vogl TJ was the involved radiologist and Marzi I the traumatologist.

Institutional review board statement: Not applicable for case reports in our instituion.

Informed consent statement: Patient gave informed consent to publication of case report.

Conflict-of-interest statement: No conflict of interest.


Correspondence to: Robin A Kaufmann, MD, Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. [email protected]: +49-69-63017277Fax: +49-69-63017258

Received: March 30, 2015 Peer-review started: April 8, 2015First decision: May 13, 2015Revised: June 23, 2015 Accepted: June 30, 2015Article in press: July 2, 2015

Published online: October 28, 2015

AbstractLigament disruptions at the craniovertebral junction are typically associated with atlantoaxial rotatory dislocation during upper cervical spine injuries and require external orthoses or surgical stabilization. Only in few patients isolated ruptures of the alar ligament have been reported. Here we present a further case, in which the diagnosis was initially obscured by a misleading clinical sympto-matology but finally established six month following the trauma, demonstrating the value of contrast-enhanced high resolution 3 Tesla magnetic resonance imaging in identifying this particular lesion.

Key words: Alar ligament rupture; Cervical spine injury; Contrast-enhanced magnetic resonance imaging


Core tip: Upper cervical spine injuries are common and bear a relevant medical and socioeconomic impact. While most of such lesions are related to atlantoaxial rotatory dislocation, thus far only few patients with isolated alar ligament ruptures have been reported. This particular trauma is a challenge to both clinicians and radiologists and diagnosis might thus be delayed. Here we present a further case of a young adult and discuss the value of sequential contrast-enhanced magnetic resonance imaging in establishing this diagnosis at a late stage and in the follow-up of a subsequently prolonged recovery.

Kaufmann RA, Marzi I, Vogl TJ. Delayed diagnosis of isolated alar ligament rupture: A case report. World J Radiol 2015; 7(10): 357-360 Available from: URL: http://www.wjgnet.com/1949-8470/

CASE REPORT






full/v7/i10/357.htm DOI: http://dx.doi.org/10.4329/wjr.v7.i10.357

INTRODUCTIONUpper cervical spine injuries are common and mainly caused by car and sport accidents or falls. They frequently are associated with longterm impairment or work disability of involved individuals and bear a relevant medical and socioeconomic impact[14]. Particularly, cases with hyperextension and rotation of the neck may eventually result in ligament ruptures, though this incident is not necessarily correlated with the intensity of the trauma[5,6]. While most of such lesions are related to atlantoaxial rotatory dislocation, thus far only few patients with isolated alar ligament ruptures have been reported[7]. Probably these cases are underdiagnosed, since they might be missed on initial presentation and only be identified in the context with persistent cervical instability. Here we present a case of a young adult and discuss the value of sequential contrastenhanced magnetic resonance imaging (MRI) in establishing this diagnosis at a late stage and in the followup of a subsequently prolonged recovery.

CASE REPORTA 25yearold man was diagnosed with rupture of the tympanic membrane of the left ear following a blunt fist hit trauma to the left side of his head associated with a short period of retro and antegrade amnesia, hearing impairment and tinnitus. While topical membrane patching led to complete healing with reestablishment of hearing, ipsilateral tinnitus remained and was accompanied by intermittent occipital pain. Moreover, during the following weeks and after repetitive sport exercises including headstands the patient developed further symptoms such as projecting aching in both shoulders, neck stiffness, dysphagia, fasciculation predominantly in the left arm, paraesthesia along the thoracic spine, neuralgiform pain attacks in the chest, few episodes of unexplainable shivering without fever and some other vague symptoms. On repetitive neurological examination there was no evidence of any objective deficits apart from an impaired neck rotation to the left side. A plain MRI excluded cervical disc herniation and except a straightening of the cervical spine reported no otherwise pathology. Mobilization and physiotherapy was advised leading to further exacerbation of symptoms. After a chiropractic manoeuvre attempted by an orthopaedic surgeon the tinnitus was felt louder and of higher frequency. An additional osteopathic treatment with repetitive sessions of rotational overstretching of the cervical spine above the tolerable pain threshold further aggravated the symptomatology. Recalling the earlier blunt injury a traumatologist was finally consulted 6 mo after the initial event who disclosed a pathologic cervical hypermobility on rotating the neck to the

right site, which was considered highly suspicious of a ligament lesion within the atlantoaxial joint. At this time a computed tomography (CT) scan ruled out a fracture or atlantooccipital dislocation but revealed a slight shift of the dens towards the right lateral mass of C1 (Figure 1). An MRI (Magnetom Prisma 3T, Siemens Healthcare) confirmed loss of lordosis on sagittal plane while the contrastenhanced axial T1weighted sequences disclosed increased signal intensity within the apex of the dens as well as within the widened left lateral densatlas space indicative of edema. Moreover, the dark signal of the left alar ligament proved to be interrupted (Figure 2), whereas the tectorial membrane and transverse ligament as well as the spinal cord appeared intact. Taken together, the findings were suggestive of an isolated rupture of the left alar ligament.

Subsequently, the cervical spine was immobilized by means of a Philadelphia collar, leading to a partial relief of the symptoms. Followup MRI of the cervical spine 3 mo later still showed signal hyperintensity within the alar ligament and the apex of the dens while its deviation apparently almost had resolved. After allowing for less cervical immobilization using a soft collar the patient’s complaint worsened again and a subsequent MRI two months later still confirmed hyperintense signalling of the involved ligament and dens. The Philadelphia collar was reintroduced and following another 3 mo of immobilization a 3rd MRI sequence showed marked improvement (Figure 3). The patient gained a progressively increasing range of neck motion in each plane and was nearly free of any discomfort except a feeling of cervical tension increasing during the day, sporadic periods of head and chest pain and persistent tinnitus of varying intensity.

DISCUSSIONIsolated unilateral alar ligament rupture is a diagnosis made by excluding associated dislocation, fracture, or disruption of other ligamentous structures in the craniovertebral junction. Only recently Wong et al[7] emphasized the special anatomical and pathophysiological aspects of this particular trauma and the value of CT and MRI to confirm the diagnosis discussing a 9 years old girl and reviewing 6 additional cases from the literature aged between 5 and 21 years, all of which fully recovered after conservative immobilization therapy within 1 year[7].

While cervical Xray, CT and MRI (T2weighted and STIR sequences) of spinal ligamentous and soft tissue trauma are normally initiated in an acute setting[8,9], in some cases appropriate imaging of cervical injuries might be missed initially or performed with delay for a variety of reasons[1012]. Also in our patient an appropriate diagnostic work-up had finally been delayed for several months, since the initial trauma and symptoms were apparently considered inadequate for further imaging analysis. MRI studies of patients with suspected occult cervical injury are well established to detect ligamentous

Kaufmann RA et al . Delayed diagnosis of isolated alar ligament rupture


injuries including the alar ligament[1315]. However, in the case presented here an earlier non contrastenhanced MRI was performed in a private practice to check exclusively for cervical disc herniation as a potential cause of the unexplained symptoms and a ligament lesion was not suspected at that time. Only after subjective symptoms worsened and were possibly linked to the earlier trauma the potential lesion became evident after simply demonstrating contralateral hypermobility on physical testing.

For an optimal detection of ligamentous lesions, the strength of the MRI has been suggested to be at least 1.5 Tesla, which corresponds to half of the magnetic field strength used in our case for an optimal resolution. A slice thickness of 2 mm is reported to give excellent spatial resolution of the injured alar ligaments[16]. Since T1weighted images provide poor contrast resolution and thus less ability to differentiate small variations in signalling we in addition used a Gadolinium contrast enhanced imaging technique. We evaluated the unenhanced and enhanced images in comparison and could better stage the amount of ligamentous injury and an

oedema of surrounding tissues.On our final MRI after initiating the 12 mo immobiliz-

ation therapy no relevant ligament or dens pathology could be documented. However, our patient still complaint of tinnitus and recurrent episodes of neck pressure, headaches and chest pain. Persisting symptoms following cervical injuries are well documented in the literature and seem likely if a healing after two years has not been achieved and more frequent in older individuals[17,18]. Whether in our patient an instant diagnosis followed by immediate external orthoses or surgical therapy according to recent recommendations would have led to an entire and earlier relief of symptoms remains however hypothetical. In conclusion, we emphasize the value of contrast high resolution 3 Tesla MRI for the detection of ligamentous injuries at the craniovertebral junction[19].

COMMENTSCase characteristicsPatient presented with neck stiffness, dysphagia, fasciculation, paraesthesia and neuralgiform pain attacks.

Clinical diagnosisFindings were suspicious of cervical ligament lesion.

Differential diagnosisSpectrum of atlantoaxial rotatory dislocation.

Imaging diagnosis3T Magnetic resonance imaging (MRI), fat-saturated gradient echo sequence (contrast-enhanced T1w fat-suppressed MRI sequence) showed a contrast enhancement in the periligamentous venous plexus with an asymmetry of the joint spaces.

Pathological diagnosisAlar ligament rupture.

TreatmentTwelve months immobilization therapy.


Figure 1 Multidetector-computed tomography coronary construction. Verification of a relationship of dens axis, atlas and occipital condyles. Asymmetry of the dento-axial joint space between left and right (white arrows) with widening on the left side. No micro- or macro-fracture.

Figure 2 High resolution contrast-enhanced 3T magnetic resonance imaging, fat-saturated gradient echo sequence performed 6 mo following the trauma. In the contrast-enhanced T1w fat-suppressed magnetic resonance imaging sequence note the contrast enhancement in the periligamentous venous plexus (arrow head). On the left side lower than on the right side. No TS symmetry of the joint space left vs right side (black and white arrow).

Figure 3 Follow-up magnetic resonance imaging. High resolution contrast-enhanced 3T magnetic resonance imaging, fat-saturated gradient echo sequence. After physical therapy stabilization. Note the clear contrast enhancement in the periligamentous venous plexus (arrow head) and the symmetric space evaluation (white arrow).

COMMENTS


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14 Ackland HM, Cameron PA, Varma DK, Fitt GJ, Cooper DJ, Wolfe R, Malham GM, Rosenfeld JV, Williamson OD, Liew SM. Cervical spine magnetic resonance imaging in alert, neurologically intact trauma patients with persistent midline tenderness and negative computed tomography results. Ann Emerg Med 2011; 58: 521-530 [PMID: 21820209 DOI: 10.1016/j.annemergmed.2011.06.008]

15 Wilmink JT, Patijn J. MR imaging of alar ligament in whiplash-associated disorders: an observer study. Neuroradiology 2001; 43: 859-863 [PMID: 11688704]

16 Krakenes J, Kaale BR, Moen G, Nordli H, Gilhus NE, Rorvik J. MRI assessment of the alar ligaments in the late stage of whiplash injury--a study of structural abnormalities and observer agreement. Neuroradiology 2002; 44: 617-624 [PMID: 12136365]

17 Gargan MF, Bannister GC. Long-term prognosis of soft-tissue injuries of the neck. J Bone Joint Surg Br 1990; 72: 901-903 [PMID: 2211780]

18 Bunketorp L, Nordholm L, Carlsson J. A descriptive analysis of disorders in patients 17 years following motor vehicle accidents. Eur Spine J 2002; 11: 227-234 [PMID: 12107791]

19 Joaquim AF, Ghizoni E, Tedeschi H, Lawrence B, Brodke DS, Vaccaro AR, Patel AA. Upper cervical injuries - a rational approach to guide surgical management. J Spinal Cord Med 2014; 37: 139-151 [PMID: 24559418 DOI: 10.1179/2045772313Y.0000000158]

P- Reviewer: Akcar N, Gumustas OG, Storto G, Sureka B S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK

Related reportsWong ST, Ernest K, Fan G, Zovickian J, Pang D. Isolated unilateral rupture of the alar ligament. J Neurosurg Pediatr 2014; 13: 541-547.

Experiences and lessonsThis particular trauma is a challenge and diagnosis might be delayed. We emphasize the value of contrast high resolution 3 Tesla MRI for the detection of ligamentous injuries at the craniovertebral junction.

Peer-reviewThe authors present a case report on a delayed diagnosis of isolated alar ligament rupture and the added value of 3 Tesla MRI for the proper assessment. The paper is well written. Appropiate iconography. The purpose is well defined and it transmits properly the message becoming of potential interest for the readers.

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World Journal of - bsdwebstorage.blob.core.windows.net · The World Journal of Radiology Editorial Board consists of 365 members, representing a team of worldwide experts in radiology