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Benign liver lesions 2022: Guideline for clinical practice of Associazione Italiana Studio del Fegato (AISF), Società Italiana di Radiologia Medica e Interventistica (SIRM), Società Italiana di Chirurgia (SIC), Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB), Associazione Italiana di Chirurgia Epatobilio-Pancreatica (AICEP), Società Italiana Trapianti d'Organo (SITO), Società Italiana di Anatomia Patologica e Citologia Diagnostica (SIAPEC-IAP) – Part I – Cystic lesions

Published:September 08, 2022DOI:https://doi.org/10.1016/j.dld.2022.08.030

      Abstract

      Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the first part of the guideline, concerning the characterization of focal hepatic lesions detected by ultrasound, and the diagnosis and clinical management of simple and parasitic hepatic cysts, and of polycystic liver disease.

      Keywords

      1. Introduction

      This report is a summary of Clinical Practice Guidelines for the management of benign liver lesions promoted by the following scientific societies: Associazione Italiana Studio del Fegato (AISF), Società Italiana di Radiologia Medica e Interventistica (SIRM), Società Italiana di Chirurgia (SIC), Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB), Associazione Italiana di Chirurgia Epatobilio-Pancreatica (AICEP), Società Italiana Trapianti d'Organo (SITO), Società Italiana di Anatomia patologica e Citologia Diagnostica (SIAPEC-IAP).
      Current knowledge on diagnosis and management of benign liver lesions is translated into relevant practical recommendations following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS).

      1.1 Clinical epidemiology of benign liver lesions

      Benign focal liver lesions are increasingly diagnosed due to the use of imaging techniques in patients with non-specific symptoms and without increased risk of liver malignancy. Therefore, in most cases they are incidental findings [
      • Orme N.M.
      • Fletcher J.G.
      • Siddiki H.A.
      • et al.
      Incidental findings in imaging research: evaluating incidence, benefit, and burden.
      ] including liver cysts and solid benign liver tumors. The latter are a heterogeneous group of lesions among which the most common are hemangioma, focal nodular hyperplasia, and adenoma, with different prevalence, clinical relevance, symptomatology, and natural course. The prevalence of benign liver lesions in the general population is approximately 15% [
      • Gore R.M.
      • Pickhardt P.J.
      • Mortele K.J.
      • et al.
      Management of incidental liver lesions on CT: a white paper of the ACR incidental findings Committee.
      ,
      • Koea J.B
      Hepatic incidentaloma: the rule of TENS.
      ,
      • Kaltenbach T.E.M.
      • Engler P.
      • Kratzer W.
      • et al.
      Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients.
      ]. Their management is a relevant clinical issue: a definition of the appropriate use of imaging, follow -up, and treatment is needed [
      • Stone J.H
      Incidentalomas–clinical correlation and translational science required.
      ].
      Based on these considerations, the problem of diagnosis and treatment of benign liver lesions was considered a priority and evaluated as such in the GRADEpro Evidence to Decision (EtD) GDT tables [
      GRADEpro gdt [Computer program] mcmaster university (developed by evidence prime) GRADEpro gdt.
      ].

      1.2 Methods for developing the guideline

      The above mentioned scientific societies whose members are primarily involved in the management of benign liver lesions selected a committee of 16 experts to draw up the guideline. This document was prepared according to the rules of the National center for clinical excellence, quality and safety of care (Centro Nazionale per l'Eccellenza Clinica, la Qualità e la Sicurezza delle Cure - CNEC) [

      CNEC - Centro Nazionale per l'Eccellenza delle Cure. Manuale metodologico per la Produzione di Linee Guida di Pratica Clinica. Roma: ISS - Istituto Superiore di Sanità - Available at: https://snlg.iss.it/wp-content/uploads/2019/04/MM_v1.3.2_apr_2019.pdf; 2020.

      ]. The committee defined the objectives and key issues. The most relevant questions were developed following the PICO format (Population, Intervention, Comparison, Outcomes), selected by discussion and voted by the whole committee. For each PICO question, the literature on MEDLINE database was systematically searched with both pertinent string and free text. A further hand-search was performed on previously published guidelines. The evidence profiles were developed applying the GRADE Evidence to Decision (EtD) framework [
      GRADEpro gdt [Computer program] mcmaster university (developed by evidence prime) GRADEpro gdt.
      ] according to the CNEC manual [

      CNEC - Centro Nazionale per l'Eccellenza delle Cure. Manuale metodologico per la Produzione di Linee Guida di Pratica Clinica. Roma: ISS - Istituto Superiore di Sanità - Available at: https://snlg.iss.it/wp-content/uploads/2019/04/MM_v1.3.2_apr_2019.pdf; 2020.

      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      GRADE guidelines: 2. Framing the question and deciding on important outcomes.
      . All aspects concerning questions, assessment of evidence, and conclusions were discussed among panel members and voted. The online GRADEpro GDT tool was used to develop questions and make decisions [
      • Moberg J.
      • Oxman A.D.
      • Rosenbaum S.
      • et al.
      GRADE Working Group
      The GRADE Evidence to Decision (EtD) framework for health system and public health decisions.
      ]. The quality of the studies was assessed applying the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) checklist for diagnostic accuracy questions [
      • Whiting P.F.
      • Rutjes A.W.
      • Westwood M.E.
      • et al.
      QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.
      ], the revised tool for Risk of Bias in randomized trials (RoB 2) [
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ], and the Risk Of Bias in Non-randomized Studies - of interventions (ROBINS-I) tool [
      • Sterne J.A.
      • Hernán M.A.
      • Reeves B.C.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ] for randomized clinical trials and non-randomized studies, where applicable.
      PICO questions and recommendations
      Focal liver lesions detected in patients without chronic liver disease or neoplastic disease
      PICO 1 - In adults without history of chronic liver disease and cancer, and with ultrasound evidence of anechoic focal liver lesions, should ultrasound with contrast agent, magnetic resonance with contrast agent, or computed tomography with contrast agent be used for an accurate diagnosis?
      Detecting hepatic cysts by ultrasound (US) or computed tomography (CT) or magnetic resonance imaging (MRI) is generally incidental. US shows a diagnostic accuracy >90% for hepatic cysts [
      • Lantinga M.A.
      • Gevers T.J.
      • Drenth J.P
      Evaluation of hepatic cystic lesions.
      ,
      • Mavilia M.G.
      • Pakala T.
      • Molina M.
      • et al.
      Differentiating cystic liver lesions: a Review of imaging modalities, diagnosis and management.
      and is able differentiating simple from complex cysts [
      • Harvey C.J.
      • Albrecht T
      Ultrasound of focal liver lesions.
      ,
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ,
      • Chernyak V.
      • Horowitz J.M.
      • Kamel I.R.
      • et al.
      Expert Panel on Gastrointestinal Imaging
      ACR appropriateness criteria® liver lesion-initial characterization.
      ]. Simple cysts show typical characteristics: anechoic content, round or oval shape, lack of intralesional septa, thin walls, and posterior acoustic reinforcement [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ,
      • Chernyak V.
      • Horowitz J.M.
      • Kamel I.R.
      • et al.
      Expert Panel on Gastrointestinal Imaging
      ACR appropriateness criteria® liver lesion-initial characterization.
      ,
      • Gaines P.A.
      • Sampson M.A
      The prevalence and characterization of simple hepatic cysts by ultrasound examination.
      ]. Only one single case of oncocytic bile duct cystic adenoma misdiagnosed as a simple cyst at US was reported [
      • Watanabe A.
      • Suzuki H.
      • Kubo N.
      • et al.
      An oncocytic variant of intraductal papillary neoplasm of the bile duct that formed a giant hepatic cyst.
      ]. Accordingly, contrast-based imaging techniques are not recommended for further characterization of simple cysts. Atypical cystic lesions, characterized by multiple or thick septa, calcifications, fenestrations, daughter cysts, irregular wall, solid papillary projections, and echo-structural heterogeneity, should be evaluated by contrast enhanced techniques, favoring MRI for lower biological risk and a probably higher diagnostic accuracy than CT [
      • Lantinga M.A.
      • Gevers T.J.
      • Drenth J.P
      Evaluation of hepatic cystic lesions.
      ,
      • Mavilia M.G.
      • Pakala T.
      • Molina M.
      • et al.
      Differentiating cystic liver lesions: a Review of imaging modalities, diagnosis and management.
      ,
      • Harvey C.J.
      • Albrecht T
      Ultrasound of focal liver lesions.
      ,
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ,
      • Chernyak V.
      • Horowitz J.M.
      • Kamel I.R.
      • et al.
      Expert Panel on Gastrointestinal Imaging
      ACR appropriateness criteria® liver lesion-initial characterization.
      ].
      Recommendation
      • a.
        In asymptomatic adults without chronic liver disease and cancer and with ultrasound evidence of anechoic focal liver lesion with the simple cyst characteristics, we suggest avoiding further evaluation with contrast-enhanced ultrasound, magnetic resonance, or computed tomography. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      • b.
        In symptomatic patients or in case of ultrasound characteristics suggesting complex cysts (presence of multiple and/or thick septa, calcifications, fenestrations, daughter cysts, irregular wall, solid papillary projections, echo-structural heterogeneity) we suggest performing a contrast-enhanced imaging technique, favoring magnetic resonance. Very low quality of evidence (D); strength of recommendation 1 (strong)
      PICO 2 - In adults without history of chronic liver disease and cancer and with ultrasound evidence of hyperechoic focal liver lesion, should magnetic resonance or computed tomography or ultrasound with contrast agent be used for an accurate diagnosis?
      At US examination, hemangiomas typically present as homogeneously hyperechoic focal lesions with well-defined margins, posterior acoustic reinforcement, and diameter < 3 cm [
      • Taboury J.
      • Porcel A.
      • Tubiana J.M.
      • et al.
      Cavernous hemangiomas of the liver studied by ultrasound. Enhancement posterior to a hyperechoic mass as a sign of hypervascularity.
      ,
      • Gandolfi L.
      • Leo P.
      • Solmi L.
      • et al.
      Natural history of hepatic haemangiomas: clinical and ultrasound study.
      . Atypical characteristics are more common in larger lesions and include hyperechoic rim delimiting a hypo- or isoechoic nodule, iso- or hypoechoic homogeneous appearance, heterogeneous echogenicity with hypoechoic areas (due to necrosis, bleeding or thrombosis) and/or calcifications [
      • McArdle C.R
      Ultrasonic appearances of a hepatic hemangioma.
      ,
      • Gandolfi L.
      • Solmi L.
      • Bolondi L.
      • et al.
      The value of ultrasonography in the diagnosis of hepatic haemangiomas.
      ,
      • Mamone G.
      • Di Piazza A.
      • Carollo V.
      • et al.
      Imaging of hepatic hemangioma: from A to Z.
      ,
      • Caseiro-Alves F.
      • Brito J.
      • Araujo A.E.
      • et al.
      Liver haemangioma: common and uncommon findings and how to improve the differential diagnosis.
      ]. In patients without chronic liver disease and cancer, the US evidence of hyperechoic lesion < 3 cm with typical characteristics of hemangioma is considered sufficient for the diagnosis, despite the lack of adequate studies and based solely on common practice [
      • Harvey C.J.
      • Albrecht T
      Ultrasound of focal liver lesions.
      ,
      • Chernyak V.
      • Horowitz J.M.
      • Kamel I.R.
      • et al.
      Expert Panel on Gastrointestinal Imaging
      ACR appropriateness criteria® liver lesion-initial characterization.
      ,
      • Colombo M.
      • Forner A.
      • Ijzermans J.
      • et al.
      EASL Clinical Practice Guidelines on the management of benign liver tumours.
      ,
      • Strauss E.
      • Ferreira Ade S.
      • França A.V.
      • et al.
      Diagnosis and treatment of benign liver nodules: brazilian Society of Hepatology (SBH) recommendations.
      ,
      • Vidili G.
      • De Sio I.
      • D'Onofrio M.
      • et al.
      SIUMB guidelines and recommendations for the correct use of ultrasound in the management of patients with focal liver disease.
      ,
      • Leifer D.M.
      • Middleton W.D.
      • Teefey S.A.
      • et al.
      Follow-up of patients at low risk for hepatic malignancy with a characteristic hemangioma at US.
      ]. In case of atypical US features, using MRI, CT or contrast-enhanced ultrasound (CEUS) is suggested to characterize the lesion. A retrospective study in patients with histological diagnosis of hemangioma showed similar accuracy for CEUS and MRI [
      • Fang L.
      • Zhu Z.
      • Huang B.
      • et al.
      A comparative study of contrast enhanced ultrasound and contrast enhanced magnetic resonance imaging for the detection and characterization of hepatic hemangiomas.
      ]. The very high sensitivity (88% and 93% respectively) and specificity (99% for both methods) appear overestimated for evident patient selection bias. Accordingly, since the quality of the studies is low, there is no evidence to choose one of the two imaging techniques [
      • Szurowska E.
      • Nowicki T.
      • Izycka-Swieszewska E.
      • et al.
      Is hepatotropic contrast enhanced MR a more effective method in differential diagnosis of hemangioma than multi-phase CT and unenhanced MR?.
      ,
      • Chung Y.E.
      • Kim M.J.
      • Kim Y.E.
      • Park M.S.
      • Choi J.Y.
      • Kim K.W
      Characterization of incidental liver lesions: comparison of multidetector CT versus Gd-EOB-DTPA-enhanced MR imaging.
      ,
      • Strobel D.
      • Seitz K.
      • Blank W.
      • et al.
      Tumor-specific vascularization pattern of liver metastasis, hepatocellular carcinoma, hemangioma and focal nodular hyperplasia in the differential diagnosis of 1,349 liver lesions in contrast-enhanced ultrasound (CEUS).
      ,
      • Trillaud H.
      • Bruel J.M.
      • Valette P.J.
      • et al.
      Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter-study in comparison to CT and MRI.
      ,
      • Kim T.
      • Federle M.P.
      • Baron R.L.
      • et al.
      Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3cm with three-phase helical CT.
      ]. After contrast agent administration, hemangiomas typically show peripheral globular enhancement followed by slow, progressive, and centripetal filling which appears complete in the late phases [
      • Mamone G.
      • Di Piazza A.
      • Carollo V.
      • et al.
      Imaging of hepatic hemangioma: from A to Z.
      ]; about 16% of hemangiomas (especially the smaller ones) show an immediate and intense contrast filling (a.k.a. flash-filling hemangioma). Rarely, hemangiomas show centrifugal filling, or absent early peripheral enhancement and very slow or absent filling (sclerotic hemangiomas). Lesions with atypical enhancement often simulate neoplastic lesions, and histology is usually required to confirm the diagnosis [
      • Mamone G.
      • Di Piazza A.
      • Carollo V.
      • et al.
      Imaging of hepatic hemangioma: from A to Z.
      ,
      • Miyamoto S.
      • Oshita A.
      • Daimaru Y.
      • et al.
      Hepatic Sclerosed Hemangioma: a case report and review of the literature.
      .
      Recommendation
      • a.
        In adults without history of chronic liver disease and cancer, in case of ultrasound evidence of hyperechoic focal lesion smaller than 3 cm with typical ultrasound characteristics of hemangioma, we suggest avoiding the use of contrast-enhanced ultrasound, magnetic resonance or computed tomography. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      • b.
        In case of atypical ultrasound characteristics or lesions > 3 cm, we suggest performing contrast-enhanced techniques for proper characterization. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 3 - In adults without history of chronic liver disease and cancer and with ultrasound evidence of hypo- or isoechoic focal liver lesion, should magnetic resonance or computed tomography or ultrasound with contrast agent be used to obtain an accurate diagnosis?
      The US detection of isoechoic or hypoechoic focal lesions does not allow a definitive diagnosis requiring a correlation with clinical-laboratory data [
      • Harvey C.J.
      • Albrecht T
      Ultrasound of focal liver lesions.
      ]. All benign lesions can appear as hypo-or isoechoic: more frequently focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), less frequently hemangiomas. Particularly, the US pattern of FNH is variable, most commonly homogeneously isoechoic and less frequently hypoechoic or hyperechoic [
      • Kehagias D.
      • Moulopoulos L.
      • Antoniou A.
      • et al.
      Focal nodular hyperplasia: imaging findings.
      ]. A central scar may be detected (45% of cases). HCA US appearance is also variable: HCAs smaller than 3–5 cm are usually isoechoic, but their appearance may vary due to bleeding, necrosis, fibrosis, or calcifications [
      • Dietrich C.F.
      • Tannapfel A.
      • Jang H.J.
      • et al.
      Ultrasound imaging of hepatocellular adenoma using the new histology classification.
      ]. Primary or secondary neoplastic lesions, incidentally detected in patients without liver disease or cancer, more commonly appear hypoechoic or isoechoic [
      • Harvey C.J.
      • Albrecht T
      Ultrasound of focal liver lesions.
      ]. Due to the different pathogenesis of hypoechoic or isoechoic lesions, contrast-enhanced techniques are needed for diagnostic characterization [
      • Chernyak V.
      • Horowitz J.M.
      • Kamel I.R.
      • et al.
      Expert Panel on Gastrointestinal Imaging
      ACR appropriateness criteria® liver lesion-initial characterization.
      ]. Contrast-enhanced MRI allows differentiating FNH from HCA, although its diagnostic accuracy, reported as > 90% and assessed in high- risk-of bias studies, is probably overestimated [
      • Grazioli L.
      • Bondioni M.P.
      • Haradome H.
      • et al.
      Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis.
      ,
      • McInnes M.D.
      • Hibbert R.M.
      • Inácio J.R.
      • et al.
      Focal nodular hyperplasia and hepatocellular adenoma: accuracy of gadoxetic acid-enhanced mr imaging-a systematic review.
      ,
      • Holzapfel K.
      • Eiber M.J.
      • Fingerle A.A.
      • et al.
      Detection, classification, and characterization of focal liver lesions: value of diffusion-weighted MR imaging, gadoxetic acid-enhanced MR imaging and the combination of both methods.
      ,
      • Margolis N.E.
      • Shaver C.M.
      • Rosenkrantz A.B
      Indeterminate liver and renal lesions: comparison of computed tomography and magnetic resonance imaging in providing a definitive diagnosis and impact on recommendations for additional imaging.
      ,
      • Alwalid O.
      • Wang Y.
      • Fan W.
      • et al.
      Value of gadoxetic acid-enhanced MR imaging and DWI in classification, characterization and confidence in diagnosis of solid focal liver lesions.
      ]. CEUS differentiates benign from malignant lesions with sensitivity of 85–100% and specificity of 63–100% [
      • von Herbay A.
      • Vogt C.
      • Häussinger D
      Late-phase pulse-inversion sonography using the contrast agent levovist: differentiation between benign and malignant focal lesions of the liver.
      ,
      • D'Onofrio M.
      • Crosara S.
      • De Robertis R.
      • Canestrini S.
      • Cantisani V.
      • Morana G.
      • Mucelli R.P
      Malignant focal liver lesions at contrast-enhanced ultrasonography and magnetic resonance with hepatospecific contrast agent.
      ,
      • Quaia E.
      • Calliada F.
      • Bertolotto M.
      • et al.
      Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride–filled microbubble contrast agent: diagnostic performance and confidence.
      ,
      • Celli N.
      • Gaiani S.
      • Piscaglia F.
      • et al.
      Characterization of liver lesions by real-time contrast-enhanced ultrasonography.
      ,
      • D'Onofrio M.
      • Martone E.
      • Faccioli N.
      • et al.
      Focal liver lesions: sinusoidal phase of CEUS.
      ], although the evidence from these studies is indirect, as patients with hyperechoic lesions or chronic liver disease or cancer were also included. In a study considering HCA as a malignant lesion, CEUS correctly identified benign hypoechoic lesions in 81% of cases, and malignant hypoechoic lesions in 88% [
      • D'Onofrio M.
      • Rozzanigo U.
      • Masinielli B.M.
      • et al.
      Hypoechoic focal liver lesions: characterization with contrast enhanced ultrasonography.
      ]. The combination of CEUS and MRI can correctly characterize 98% of liver lesions [
      • Moriyasu F.
      • Itoh K
      Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial.
      ]. Contrast-enhanced CT has a diagnostic accuracy of 80–88% [
      • Moriyasu F.
      • Itoh K
      Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial.
      ,
      • Seitz K.
      • Strobel D.
      • Bernatik T.
      • et al.
      Contrast-Enhanced Ultrasound (CEUS) for the characterization of focal liver lesions - prospective comparison in clinical practice: CEUS vs. CT (DEGUM multicenter trial).
      , lower than that of MRI [
      • Margolis N.E.
      • Shaver C.M.
      • Rosenkrantz A.B
      Indeterminate liver and renal lesions: comparison of computed tomography and magnetic resonance imaging in providing a definitive diagnosis and impact on recommendations for additional imaging.
      ].
      Recommendation
      In adults without chronic liver disease and cancer, in case of ultrasound evidence of hypo- or isoechoic focal lesion, we suggest performing magnetic resonance or computed tomography or ultrasound with contrast agent to obtain an accurate diagnosis. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 4 - In adults without chronic liver disease and cancer and with a solid focal liver lesion not definitively characterized by contrast-enhanced imaging techniques, should a percutaneous biopsy of the lesion be performed to obtain an accurate diagnosis?
      The decision to biopsy a focal liver lesion not definitively characterized with imaging techniques in patients without chronic liver disease or cancer is not supported by the available data. Indeed, no study was found reporting the frequency of non-diagnostic results of imaging techniques. A multidisciplinary team might better evaluate the decision, considering potential complications and benefits of lesion characterization. Patient data (age, gender, risk factors, clinical picture, laboratory tests) and lesion data (imaging findings, size, visibility, accessibility for US or CT-guided biopsy) influence the choice between biopsy, imaging surveillance, or immediate surgery [
      • Pang E.H.
      • Harris A.C.
      • Chang S.D
      Approach to the Solitary Liver Lesion: imaging and When to Biopsy.
      ]. Percutaneous liver biopsy does involve risks. The risk of mortality is 0.02% [
      • West J.
      • Card T.R
      Reduced mortality rates following elective percutaneous liver biopsies.
      ], and the bleeding risk 0.1%−1.7% [
      • Midia M.
      • Odedra D.
      • Shuster A.
      • et al.
      Predictors of bleeding complications following percutaneous image-guided liver biopsy: a scoping review.
      ]. The risk of needle tract seeding of malignant lesions has been estimated 2.3%−2.7% in patients with HCC [
      • Stigliano R.
      • Marelli L.
      • Yu D.
      • et al.
      Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC.
      ,
      • Silva M.A.
      • Hegab B.
      • Hyde C.
      • et al.
      Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis.
      , 6% in metastatic colon cancer patients and 0% in metastatic breast cancer patients [
      • Chen I.
      • Lorentzen T.
      • Linnemann D.
      • et al.
      Seeding after ultrasound-guided percutaneous biopsy of liver metastases in patients with colorectal or breast cancer.
      ]. A retrospective study showed that CEUS guidance is more effective than US guidance for diagnosing malignancy in indeterminate lesions (100% vs 74%) [
      • Cresswell A.B.
      • Welsh F.K.
      • Rees M
      A diagnostic paradigm for resectable liver lesions: to biopsy or not to biopsy?.
      ]. Fusion image-guided techniques of US with CT or MRI for poorly visualized lesions showed technical success rate of 96% [
      • Park H.J.
      • Lee M.W.
      • Lee M.H.
      • et al.
      Fusion imaging-guided percutaneous biopsy of focal hepatic lesions with poor conspicuity on conventional sonography.
      ].
      Fig. 1 shows a proposed flow-chart for the characterization of focal liver lesions detected by ultrasound in patients with negative history of chronic liver disease or cancer.
      Fig 1
      Fig. 1Flow-chart concerning the recommended sequence of imaging and biopsy techniques to be used for the characterization of focal liver lesions detected by ultrasound in patients without chronic liver disease and/or neoplastic diseases.
      Abbreviations: US: ultrasound; CT: computed tomography; MRI: magnetic resonance imaging; CEUS: contrast enhanced ultrasound.
      Recommendation
      In adults without chronic liver disease and cancer and with solid focal liver lesions not characterized by imaging techniques, we suggest a multidisciplinary discussion to assess if biopsy could influence the therapeutic decisions. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      Simple cyst
      Simple hepatic cysts are congenital lesions arising from aberrant bile duct, not communicating with the biliary tree, in which endoluminal fluid secretions progressively accumulate [
      • Drenth J.P.
      • Chrispijn M.
      • Nagorney D.M.
      • et al.
      Medical and surgical treatment options for polycystic liver disease.
      ]. Most of them are < 3 cm, but larger cysts can reach 30 cm in diameter [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ,
      • Sanfelippo P.M.
      • Beahrs O.H.
      • Weiland L.H
      Cystic disease of the liver.
      . Multiple cysts are common in the same patient, but this condition is distinguished from polycystic liver disease (PLD), which is characterized by more than 20 cysts. The incidence is higher in adults over 40–50 years, with female/male ratio of 4:1 [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ]. The prevalence ranges between 2.5% and 18% in adults [
      • Kaltenbach T.E.M.
      • Engler P.
      • Kratzer W.
      • et al.
      Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients.
      ,
      • Gaines P.A.
      • Sampson M.A
      The prevalence and characterization of simple hepatic cysts by ultrasound examination.
      ,
      • Carrim Z.I.
      • Murchison J.T
      The prevalence of simple renal and hepatic cysts detected by spiral computed tomography.
      with a clear trend to increase with age [
      • Kaltenbach T.E.M.
      • Engler P.
      • Kratzer W.
      • et al.
      Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients.
      ,
      • Larssen T.B.
      • Rørvik J.
      • Hoff S.R.
      • et al.
      The occurrence of asymptomatic and symptomatic simple hepatic cysts. A prospective, hospital-based study.
      .
      PICO 5 - In asymptomatic adult patients with an imaging diagnosis of simple cyst is follow-up required?
      The incidental detection of simple cysts in asymptomatic patients without history of neoplastic disease requires no treatment nor follow-up. Indeed, it has been shown that there is no risk of malignant transformation [
      • Terada T.
      • Nakanuma Y.
      • Ohta
      • et al.
      Mucin-histochemical and immunohistochemical profiles of epithelial cells of several types of hepatic cysts.
      ], The benefit of surveillance cannot be demonstrated and does not justify the costs. The recommendation is based on the opinion generated by clinical practice rather than systematic follow-up studies [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ,
      • Strauss E.
      • Ferreira Ade S.
      • França A.V.
      • et al.
      Diagnosis and treatment of benign liver nodules: brazilian Society of Hepatology (SBH) recommendations.
      .
      Recommendation
      In asymptomatic adults with simple cysts and negative history of malignancy we suggest avoiding follow-up. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 6 - In adults with complex cysts, are cytologic or histologic examinations indicated for a more accurate diagnostic characterization?
      The few available data suggest a low sensitivity of cytologic and histologic examinations [
      • Pinto M.M.
      • Kaye A.D
      Fine needle aspiration of cystic liver lesions. Cytologic examination and carcinoembryonic antigen assay of cyst contents.
      ]. The diagnosis of mucinous cystic tumor (aka biliary cystadenoma) requires the identification of the stroma which can not be obtained by cyto-aspiration; furthermore, neoplastic areas are often focally distributed with low probability of being sampled [
      • Quigley B.
      • Reid M.D.
      • Pehlivanoglu B.
      • et al.
      Hepatobiliary mucinous cystic neoplasms with ovarian type stroma (So-Called “Hepatobiliary Cystadenoma/Cystadenocarcinoma”) clinicopathologic analysis of 36 cases illustrates rarity of carcinomatous change.
      ,
      WHO Classification of Tumors Editorial Board
      Digestive System Tumors.
      . The same considerations apply to the differential diagnosis between intraductal papillary neoplasm and intraductal papillary neoplasm with invasive component.
      Recommendation
      In adults with complex cysts, we suggest not performing a cyto-aspirate or a needle biopsy due to low diagnostic sensitivity. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 7 - In adults with complex cysts, should surgical treatment versus follow-up be indicated?
      Differential diagnosis of complex hepatic cysts includes mucinous cystic tumor and simple cysts with previous intra-cystic bleeding [
      • Soares K.C.
      • Arnaoutakis D.J.
      • Kamel I.
      • et al.
      Cystic neoplasms of the liver: biliary cystadenoma and cystadenocarcinoma.
      ]. In case of radiological suspicion of mucinous cystic tumor, surgery with complete excision of the cyst is the preferred treatment as the estimated risk of malignant transformation is 25%, and simple fenestration is associated with high risk of relapse [
      • Arnaoutakis D.J.
      • Kim Y.
      • Pulitano C.
      • et al.
      Management of biliary cystic tumors: a multi-institutional analysis of a rare liver tumor.
      ].
      Recommendation
      In adults diagnosed with complex cysts, we suggest surgical treatment. In case of preoperative radiological suspicion of mucinous cystic tumor, the complete excision of the cysts (enucleation or liver resection, depending on the site) should be performed. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 8 - In symptomatic patients with simple cysts does treatment offer better results than follow-up?
      Most common symptoms are abdominal pain, nausea, vomiting, and postprandial swelling. Symptoms are rarely associated with complications such as bleeding or abscess formation. A retrospective study compared symptoms recurrence in patients undergoing surgery or conservative treatment and showed a lower rate of recurrence after surgical treatment [
      • de Reuver P.
      • van der Walt I.
      • Albania M.
      • et al.
      Long-term outcomes and quality of life after surgical or conservative treatment of benign simple liver cysts.
      ]. Furthermore, a retrospective study, lacking a control arm, showed that surgery improves the quality of life in symptomatic patients with simple cysts [
      • Janssen Y.F.
      • Haring M.P.D.
      • Bastiaannet E.
      • et al.
      Surgical treatment for non-parasitic liver cysts improves quality of life.
      ].
      Recommendation
      We suggest treating symptomatic patients with simple cysts to improve the quality of life. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 9 - In symptomatic patients with simple cysts does surgical treatment offer better results than percutaneous treatment?
      Percutaneous aspiration of the cyst is effective only when intra-cystic instillation of sclerosing agents (such as ethanol, minocycline, tetracycline or polidicanol) is performed after inoculation of contrast agent excluding biliary communication. Nowadays, the surgical treatment of choice is laparoscopic fenestration that is as effective as laparotomic fenestration and is associated with symptomatic relief in 90.2% of cases, symptomatic recurrence in 9.6%, and reintervention in 7.1% [
      • Bernts L.H.P.
      • Echternach S.G.
      • Kievit W.
      • et al.
      Clinical response after laparoscopic fenestration of symptomatic hepatic cysts: a systematic review and meta-analysis.
      ]. Concerning the comparison between percutaneous aspiration with sclerotherapy (PAS) and surgical treatment, the quality of evidence is very low due to the lack of randomized comparative studies. In a retrospective study, PAS and laparoscopic fenestration were equally effective in achieving partial or complete cyst obliteration [
      • Moorthy K.
      • Mihssin N.
      • Houghton P.W
      The management of simple hepatic cysts: sclerotherapy or laparoscopic fenestration.
      ]. In a systematic review, the ratio of persistent symptoms was higher after PAS compared to laparoscopic fenestration (3.5% vs. 2.1%), but major complication (1.7% vs. 0.8%) and post-treatment relapse (5.5% vs. 0%) were higher in patients treated with laparoscopic fenestration. To note, the mean size of the cysts was smaller (9.3 vs 12.7 cm) and the mean follow-up was shorter (26 vs 38 months) in the PAS group than in the surgical group [
      • Furumaya A.
      • van Rosmalen B.V.
      • de Graeff J.J.
      • et al.
      Systematic review on percutaneous aspiration and sclerotherapy versus surgery in symptomatic simple hepatic cysts.
      ].
      Recommendation
      In symptomatic patients with simple cysts, the available data fail to demonstrate superiority of surgical (laparoscopic fenestration) over percutaneous treatment (aspiration and sclerotherapy). Both treatments are effective. We suggest that the choice between the two options considers the size and location of the cyst, the experience of the center, the comorbidities, and the preferences of the patient. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 10 - a) In symptomatic patients with simple cysts does laparoscopic fenestration offer better results than liver resection? b) In symptomatic patients with recurrent simple cysts does liver resection offer better results than laparoscopic fenestration?
      One retrospective study identified 40 consecutive patients with simple cysts treated by laparoscopic or laparotomic fenestration or liver resection. The laparoscopic fenestration group showed lower postoperative morbidity and length of hospital stay. At median follow up of 20 months, there were no recurrences in the resection group, while recurrence occurred in 22% of patients in the fenestration group; only two of these patients required a resection [
      • Tan Y.M.
      • Chung A.
      • Mack P.
      • Chow P.
      • Khin L.W.
      • Ooi L.L
      Role of fenestration and resection for symptomatic solitary liver cysts.
      ]. In another retrospective study, 67 symptomatic simple cysts were treated with laparoscopic deroofing (48 cases), open deroofing (11 cases), and resection (12 cases). Recurrence occurred in 29%, 36%, and 27% of cases, respectively, with 4% of patients who had further surgery in the laparoscopic deroofing group, 18% in the open deroofing group, and none in the resection group [
      • Gall T.M.
      • Oniscu G.C.
      • Madhavan K.
      • et al.
      Surgical management and longterm follow-up of non-parasitic hepatic cysts.
      ]. There are no studies comparing treatments of recurrence after fenestration, therefore resection is preferred over fenestration, based on the absence of recurrence in resected patients in the above-quoted studies.
      Recommendation
      • a.
        In patients with symptomatic simple cysts laparoscopic fenestration is preferred over liver resection. Very low quality of evidence (D); strength of recommendation 2 (conditional).
      • b.
        In symptomatic patients with simple cysts recurrent after fenestration liver resection is preferred over fenestration. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      Polycystic liver disease
      Polycystic liver disease (PLD) is a genetic condition characterized by the development of more than 20 hepatic cysts [
      • Marrero J.A.
      • Ahn J.
      • Rajender Reddy K.
      • et al.
      ACG clinical guideline: the diagnosis and management of focal liver lesions.
      ,
      • Khan S.
      • Dennison A.
      • Garcea G
      Medical therapy for polycystic liver disease.
      . PLD occurs in two forms depending on the presence or absence of autosomal dominant polycystic kidney disease (ADPKD) [
      • van Aerts R.
      • van de Laarschot L.
      • Banales J.M.
      • et al.
      Clinical management of polycystic liver disease.
      ]. Both conditions present a dominant autosomal pattern of inheritance. PLD associated with ADPKD is linked to mutations of the PKD1 or PKD2 gene, while in PLD not associated with ADPKD - aka autosomal dominant polycystic liver disease (ADPLD)- heterozygous mutations of the genes PRKCSH or SEC63 are present [
      • Drenth J.P.
      • te Morsche R.H.
      • Smink R.
      • Bonifacino J.S.
      • Jansen J.B
      Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease.
      ,
      • Li A.
      • Davila S.
      • Furu L.
      • et al.
      Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease.
      ,
      • Drenth J.P.
      • Martina J.A.
      • Te Morsche R.H.
      • Jansen J.B.
      • Bonifacino J.S
      Molecular characterization of hepatocystin, the protein that is defective in autosomal dominant polycystic liver disease.
      ,
      • Rossetti S.
      • Consugar M.B.
      • Chapman A.B.
      • et al.
      Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.
      ,
      • Waanders E.
      • Venselaar H.
      • Te Morsche R.H.
      • et al.
      Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63.
      ,
      • Janssen M.J.
      • Waanders E.
      • Woudenberg J.
      • et al.
      Congenital disorders of glycosylation in hepatology: the example of polycystic liver disease.
      ]. Both conditions are included among the hepatorenal fibrocystic diseases or ciliopathies [
      • Waanders E.
      • Venselaar H.
      • Te Morsche R.H.
      • et al.
      Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63.
      ,
      • Chandok N
      Polycystic liver disease: a clinical review.
      . ADPKD is the most common monogenetic kidney disease (with a prevalence of 1:400- 1:1000) and is associated with PLD in 20%−75% of cases [
      • Temmerman F.
      • Missiaen L.
      • Bvammens B.
      • et al.
      Systematic review: the pathophysiology and management of polycistic liver disease.
      ]. The prevalence of isolated ADPLD is lower, approximately 1:100.000 [
      • Temmerman F.
      • Missiaen L.
      • Bvammens B.
      • et al.
      Systematic review: the pathophysiology and management of polycistic liver disease.
      ,
      • Wong M.Y.
      • McCaughan G.W.
      • Strasser S.I
      An update on the pathophysiology and management of polycystic liver disease.
      ,
      • Torres V.E.
      • Harris P.C.
      • Pirson Y
      Autosomal dominant polycystic kidney disease.
      ,
      • Sherstha R.
      • McKinley C.
      • Russ P.
      • et al.
      Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.
      ].
      In more than 80% of cases, PLD is asymptomatic. Typical symptoms are abdominal distension and pain, early satiety, nausea, dyspnea, lower limbs’ edema, and ascites. In PLD, cysts grow slowly, and their volume increase rate is between 0.9 and 3.2% /year [
      • Drenth J.P.
      • Chrispijn M.
      • Nagorney D.M.
      • et al.
      Medical and surgical treatment options for polycystic liver disease.
      ,
      • Hogan M.C.
      • Masyuk T.V.
      • Page L.J.
      • et al.
      Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
      ,
      • van Keimpema L.
      • Nevens F.
      • Vanslembrouck R.
      • et al.
      Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.
      . Gender is associated with disease severity: women account for more than 80% of symptomatic patients with PLD [
      • van Keimpema L.
      • De Koning D.B.
      • Van Hoek B.
      • et al.
      Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases.
      ] and the large majority (> 80%) of PLD patients receiving liver transplant are women [
      • van Keimpema L.
      • Nevens F.
      • Adam R.
      • et al.
      Excellent survival after liver transplantation for isolated polycystic liver disease: an European liver transplant registry study.
      ]. These gender-related differences can be related to the hormonal status [
      • Sherstha R.
      • McKinley C.
      • Russ P.
      • et al.
      Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.
      ,
      • Gabow P.A.
      • Johnson A.M.
      • Kaehny W.D.
      • et al.
      Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease.
      ,
      • Chebib F.T.
      • Jung Y.
      • Heyer C.M.
      • et al.
      Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease.
      ,
      • Hogan M.C.
      • Abebe K.
      • Torres V.E.
      • et al.
      Liver involvement in early autosomal-dominant polycystic kidney disease.
      ]. In ADPLD liver failure and liver-related death are rare, whereas liver failure is the cause of death in 10% of ADPKD patients [
      • Temmerman F.
      • Missiaen L.
      • Bvammens B.
      • et al.
      Systematic review: the pathophysiology and management of polycistic liver disease.
      ]. Cyst complications are rare and include rupture, bleeding, and infection. [
      • Marion Y.
      • Brevartt C.
      • Plard L.
      • et al.
      Hemorrhagic liver cyst rupture: an unusual life-threatening complication of hepatic cyst and literature review.
      ]. Liver test abnormalities (with either hepatocellular or cholestatic pattern) are common in symptomatic patients [
      • Arnold H.L.
      • Harrison S.A
      New advances in evaluation and management of patients with polycystic liver disease.
      ]. PLD patients can present with portal hypertension resulting from compression of the portal branches or hepatic veins; its development was demonstrated during follow up in 6% of cases [
      • van Keimpema L.
      • De Koning D.B.
      • Van Hoek B.
      • et al.
      Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases.
      ] and in 40% of patients listed for liver transplantation [
      • Rajoriya N.
      • Tripathi D.
      • Leithead J.A.
      • Gunson B.K.
      • Lord S.
      • Ferguson J.W.
      • Hirschfield G.M
      Portal hypertension in polycystic liver disease patients does not affect wait-list or immediate post-liver transplantation outcomes.
      ,
      • Bernts L.H.P.
      • Drenth J.P.H.
      • Tjwa E.T.T.L
      Management of portal hypertension and ascites in polycystic liver disease.
      .
      Ultrasound highlights multiple fluid-containing, anechoic, round or oval, sharp-edged formations with posterior wall reinforcement [
      • Arnold H.L.
      • Harrison S.A
      New advances in evaluation and management of patients with polycystic liver disease.
      ]. The total liver volume is evaluated with CT or MRI and is a prognostic marker. Two classifications of mild, moderate and severe phenotypes based on the patient's height-adjusted total liver volume (htTLV) are available [
      • Hogan M.C.
      • Abebe K.
      • Torres V.E.
      • et al.
      Liver involvement in early autosomal-dominant polycystic kidney disease.
      ,
      • Kim H.
      • Park H.C.
      • Ryu H.
      • et al.
      Clinical correlates of mass effect in autosomal dominant polycystic kidney disease.
      . According to Kim classification, disease severity is classified as mild (htTLV <1600 mL/m), moderate (htTLV 1600–3200 mL/m), and severe (htTLV > 3200 mL/m) [
      • Kim H.
      • Park H.C.
      • Ryu H.
      • et al.
      Clinical correlates of mass effect in autosomal dominant polycystic kidney disease.
      ].
      PICO 11 - In asymptomatic relatives of patients with isolated polycystic liver disease, should ultrasound screening be indicated for early diagnosis?
      PLD penetrance is incomplete and 20% of mutation carriers may not phenotypically experience the disease. Genetic tests and family screening in ADPLD do not influence individual clinical management [
      • van Aerts R.
      • van de Laarschot L.
      • Banales J.M.
      • et al.
      Clinical management of polycystic liver disease.
      ]. Indeed, therapy is only indicated for symptomatic patients with moderate- severe disease and reduced quality of life. In the absence of treatments able to modify the disease course in asymptomatic patients, ultrasound screening in asymptomatic relatives of PLD patients is not currently indicated.
      Recommendation
      In asymptomatic relatives of individuals with isolated polycystic liver disease, we suggest no ultrasound screening. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 12 - In adults with ultrasound diagnosis of polycystic liver disease, should magnetic resonance with contrast agent be indicated for staging and differential diagnosis from other diseases such as bile duct hamartomas, peribiliary cysts, and Caroli disease?
      A diagnosis of PLD can be made identifying more than 20 hepatic cysts with US, CT, or MRI. CT and MRI also allow staging by assessing: a) intrahepatic extent of disease; b) involvement of other abdominal organs; c) cyst complications. MRI cholangiography with hepato-specific contrast agent allows an appropriate differential diagnosis from other cystic diseases of the liver, such as Caroli disease, [
      • Drenth J.P.
      • Chrispijn M.
      • Nagorney D.M.
      • et al.
      Medical and surgical treatment options for polycystic liver disease.
      ,
      • Ishak K.G.
      • Sharp H.L
      Developmental abnormalities and liver disease in childhood.
      ,
      • Cnossen W.R.
      • Drenth J.P
      Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.
      ,
      • Salvadori P.S.
      • Torres U.S.
      • D'Ippolito G
      Contrast-enhanced magnetic resonance cholangiography with gadoxetic-acid-disodium for the detection of biliary-cyst communication in Caroli disease.
      ], bile duct hamartomas (Von Meyenburg complexes) [
      • Mortelè K.J.
      • Ros P.R
      Cystic focal liver lesions in the adult: differential CT and MR imaging features.
      ,
      • Patel N.J.
      • Caserta M.P.
      • Di Santis D.J
      The "starry sky" liver.
      ,
      • Mortelé B.
      • Mortelé K.
      • Seynaeve P.
      • et al.
      Hepatic bile duct hamartomas (von Meyenburg Complexes): MR and MR cholangiography findings.
      ] and hepatic peribiliary cysts [
      • Kudo M
      Hepatic peribiliary cysts: clinically harmless disease with potential risk due to gradual increase in size and number.
      ].
      Recommendation
      In patients with ultrasound diagnosis of polycystic liver disease, we suggest magnetic resonance with hepato-specific contrast agent for appropriate differential diagnosis from other fibro-polycystic liver diseases (bile duct hamartomas and Caroli disease), from peribiliary cysts, and for staging the disease. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 13 - In adults with asymptomatic polycystic liver disease, does surgical (laparoscopic fenestration) or percutaneous (aspiration and sclerotherapy) treatment give better results than follow-up?
      The dedicated and validated questionnaires POLCA and PLD-Q can be used to assess the symptoms burden and the need of treatment [
      • Temmerman F.
      • Dobbels F.
      • Ho T.A.
      • et al.
      Development and validation of a polycystic liver disease complaint-specific assessment (POLCA).
      ,
      • Neijenhuis M.K.
      • Gevers T.J.
      • Hogan M.C.
      • et al.
      Development and validation of a disease-specific questionnaire to assess patient-reported symptoms in polycystic liver disease.
      . The Sequential Organ Failure Assessment (SOFA) has recently been developed to screen patients with PLD at risk for sepsis [
      • Jouret F.
      • Hogan M.C.
      • Chebib F.T
      A practical guide for the management of acute abdominal pain with fever in patients with autosomal dominant polycystic kidney disease.
      ]. In rare cases treatment may be considered in asymptomatic patients with dominant cysts causing compression and distortion of intra- or perihepatic anatomical structures [
      • Mikolajczyk A.E.
      • Te H.S.
      • Chapman A.B
      Gastrointestinal manifestations of autosomal-dominant polycystic kidney disease.
      ].
      Recommendation
      In adults with asymptomatic polycystic liver disease, follow-up with periodic administration of dedicated symptom-assessment questionnaires is suggested. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 14 - In adults with symptomatic polycystic liver disease, does treatment with somatostatin analogues give better results than follow-up?
      In a randomized, double-blind, controlled trial, 54 patients with ADPLD or with PLD associated with ADPKD received lanreotide (120 mg) or placebo every 28 days for 24 weeks. Lanreotide group showed a significant reduction in liver volume compared to placebo group [
      • van Keimpema L.
      • Nevens F.
      • Vanslembrouck R.
      • et al.
      Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.
      ]. In a recent meta-analysis including 6 trials (592 patients), somatostatin analogues significantly reduced TLV. The same meta-analysis suggests an advantage of lanreotide over octreotide, but the small number of studies prevents to draw definitive conclusions [
      • Griffiths J.
      • Mills M.T.
      • Ong A.C
      Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis.
      ]. The lanreotide dosage of 120 mg every 4 weeks was more effective than 90 mg every 4 weeks. However, the lower dose showed fewer side effects and then could be used in case of intolerance to the higher dose [
      • Temmerman F.
      • Gevers T.
      • Ho T.A.
      • et al.
      Safety and efficacy of different lanreotide doses in the treatment of polycystic liver disease: pooled analysis of individual patient data.
      ]. Finally, a summary analysis of 107 patients with PLD from 3 randomized controlled trials showed that females are the subgroup with the best response to somatostatin analogue [
      • Gevers T.J.
      • Inthout J.
      • Caroli A.
      • et al.
      Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data.
      ].
      Recommendation
      In adults with symptomatic polycystic liver disease, we suggest treatment with somatostatin analogues as it provides reduction of liver volume and symptoms compared to follow-up. Low quality of evidence (C); strength of recommendation 2 (conditional)
      PICO 15 - In adults with polycystic liver disease and one or more symptomatic dominant cysts, is surgical treatment more effective than percutaneous treatment for symptoms remission?
      Retrospective studies showed that surgical treatment is effective in remission of symptoms in patients with PLD and dominant cysts [
      • Bernts L.H.P.
      • Neijenhuis M.K.
      • Edwards M.E.
      • et al.
      Symptom relief and quality of life after combined partial hepatectomy and cyst fenestration in highly symptomatic polycystic liver disease.
      ,
      • Chebib F.T.
      • Harmon A.
      • Irazabal Mira M.
      • et al.
      Outcomes and durability of hepatic reduction after combined partial hepatectomy and cyst fenestration for massive polycystic liver disease.
      ,
      • Yang J.
      • Ryu H.
      • Han M.
      • et al.
      Comparison of volume-reductive therapies for massive polycystic liver disease in autosomal dominant polycystic kidney disease.
      ,
      • Boillot O.
      • Cayot B.
      • Guillaud O.
      • et al.
      Partial major hepatectomy with cyst fenestration for polycystic liver disease: indications, short and long-term outcomes.
      ,
      • Gigot J.F.
      • Jadoul P.
      • Que F.
      • et al.
      Adult polycystic liver disease: is fenestration the most adequate operation for long-term management?.
      ]. A systematic review and meta-analysis of the efficacy of laparoscopic fenestration of symptomatic cysts included 15 studies with PLD patients. The postoperative complications was more frequent than in patients with solitary cysts [
      • Bernts L.H.P.
      • Echternach S.G.
      • Kievit W.
      • et al.
      Clinical response after laparoscopic fenestration of symptomatic hepatic cysts: a systematic review and meta-analysis.
      ]. PAS is also effective and in a recent systematic review, symptoms reduction and disappearance were observed in 72% and 59% of patients with PLD, compared with 94% and 82% in patients with solitary cysts. The most frequent side effects were post-procedural pain and bleeding [
      • Wijnands T.F.
      • Görtjes A.P.
      • Gevers T.J.
      • et al.
      Efficacy and safety of aspiration sclerotherapy of simple hepatic cysts: a systematic review.
      ].
      Recommendation
      In adults with polycystic liver disease and one or more symptomatic dominant cysts, the available data fail to demonstrate a superiority of the surgical (laparoscopic fenestration/surgical resection) over percutaneous treatment (aspiration associated with sclerotherapy preceded by contrast exclusion of communication between the treated cyst and the biliary tree). Both treatments are effective, and we suggest that the choice between the two options should consider the size and the location of cysts, the experience of the center, the presence of comorbidities, and the preferences of the patient. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 16 - In adults with polycystic liver disease and clinically relevant symptoms or measurable impairment of the quality of life, is liver transplantation more effective than other treatments?
      Liver transplantation is the only curative treatment but should be considered in a minority of patients with massive hepatomegaly associated with severe malnutrition or other serious complications (recurrent cysts bleeding/infection, portal hypertension causing untreatable ascites) and when poor effectiveness of non-transplant therapies can be anticipated [
      • van Aerts R.
      • van de Laarschot L.
      • Banales J.M.
      • et al.
      Clinical management of polycystic liver disease.
      ,
      • Aussilhou B.
      • Dokmak S.
      • Dondero F.
      • et al.
      Treatment of polycystic liver disease. Update on the management.
      ,
      • Starzl T.E.
      • Reyes J.
      • Tzakis A.
      • Mieles L.
      • Todo S.
      • Gordon R
      Liver transplantation for polycystic liver disease.
      . In addition, the indication may arise from severely and objectively compromised quality of life [
      • Russell R.T.
      • Pinson C.W
      Surgical management of polycystic liver disease.
      ]. Survival at 1 and 5 years for combined liver and kidney transplantation is 86% and 80%, and for liver transplantation alone 93% and 92% [
      • van Keimpema L.
      • Nevens F.
      • Adam R.
      • et al.
      Excellent survival after liver transplantation for isolated polycystic liver disease: an European liver transplant registry study.
      ]. Even more recently, 100% probability of survival at 1 year and 96% at 3, 5, and 10 years have been reported [
      • Alsager M
      • Neong S.F.
      • Gandhi R
      • et al.
      Liver transplantation in adult polycystic liver disease: the Ontario experience.
      ].
      Recommendation
      In adults with massive polycystic liver disease (cyst/liver parenchyma volume ratio > 1) and clinically relevant symptoms such as severe malnutrition, complications of portal hypertension, severe cholestasis, recurrent cysts hemorrhage/infection, or impaired quality of life, we suggest liver transplantation. Low quality of evidence (C); strength of recommendation 2 (conditional)
      Parasitic cyst
      Cystic echinococcosis (CE) -aka “hydatid disease” or “hydatidosis”- is an infestation caused by Echinococcus granulosus, a parasite that has canids as definitive host and humans and other animals (especially cattle and sheep) as intermediate hosts [
      • Deplazes P.
      • Rinaldi L.
      • Alvarez Rojas C.A.
      • et al.
      Global distribution of alveolar and cystic echinococcosis.
      ]. Humans and ungulates are infected by ingesting embryonated eggs, shed from the feces of final hosts. CE has a global geographic distribution and cases are reported in all continents, except Antarctica [
      • Deplazes P.
      • Rinaldi L.
      • Alvarez Rojas C.A.
      • et al.
      Global distribution of alveolar and cystic echinococcosis.
      ].
      After eggs ingestion by an intermediate host, the embryos hatch, penetrate the intestinal wall, enter blood or lymphatic vessels, and reach the target organs where develop to larval stage oncospheres (metacestode) and form a single chamber cyst that slowly expands and progresses from a fluid-filled unilocular cavity to a pseudo-solid, eventually calcified, lesion [
      • Romig T.
      • Deplazes P.
      • Jenkins D.
      • et al.
      Ecology and Life Cycle Patterns of Echinococcus Species.
      ]. The liver is the organ most frequently involved (69–75% of cases). Cyst development is usually clinically silent, but abdominal pain, dyspepsia, fever, and allergic manifestations may occur. Complications of active cysts are frequent and include rupture in the biliary tree or in the peritoneum, infection, and biliary fistula [
      • Macpherson C.N.L.
      • Mengiste A.
      • Zeyhle E.
      • et al.
      Cystic Echinococcosis in Turkana, Kenya: the role of cross-sectional screening surveys in assessing the prevalence of human infection.
      ,
      • Rinaldi F.
      • Brunetti E.
      • Neumayr A.
      • et al.
      Cystic echinococcosis of the liver: a primer for hepatologists.
      ,
      • Collado-Aliaga J.
      • Romero-Alegría Á.
      • Alonso-Sardón M.
      • et al.
      Complications associated with initial clinical presentation of cystic echinococcosis: a 20-year cohort analysis.
      ].
      US is the first-choice technique for diagnosing abdominal CE, with high sensitivity (93–98%) and specificity (88–90%) [
      • MacPherson C.N.
      • Romig T.
      • Zeyhle E.
      • et al.
      Portable ultrasound scanner versus serology in screening for hydatid cysts in a nomadic population.
      ,
      • Macpherson C.N.
      • Bartholomot B.
      • Frider B
      Application of ultrasound in diagnosis, treatment, epidemiology, public health and control of Echinococcus granulosus and E. multilocularis.
      ,
      • Caremani M.
      • Benci A.
      • Maestrini R.
      • et al.
      Ultrasound imaging in cystic echinococcosis. Proposal of a new sonographic classification.
      ]. The classification of the WHO-Informal Working Group on Echinococcosis (WHO-IWGE) allows for a stage-specific treatment approach [
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      • et al.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ]. The cyst stages are the following: CE1 (active stage): uniformly anechoic cyst with wall that may consist of two hyperechoic lines separated by hypoechoic layer; fine echoes may be seen inside the cyst (“hydatid sand”); CE2 (active stage): multiple (daughter) cysts delimited by septa seen within the main cavity (“honeycomb pattern”); CE3a (transitional stage): uniform fluid collection with floating layers displaying detachment of endocyst from pericyst (“water-lily sign”); CE3b (active stage): predominantly solid cysts with embedded daughter cysts; CE4 (inactive stage): the matrix fills the cyst completely, but wavy lines (folded endocyst) confer a “ball of wool” appearance; CE5 (inactive stage): the cyst is completely solid and with an eggshell calcification. MRI allows assessing extra abdominal or abdominal cysts that cannot be visualized with US and may be used alone or in combination with CT scan for suspected complications [
      • Oto A.
      • Akhan O.
      • Ozmen M
      Focal inflammatory diseases of the liver.
      ,
      • Greco S.
      • Cannella R.
      • Giambelluca D.
      • et al.
      Complications of hepatic echinococcosis: multimodality imaging approach.
      .
      To date, four treatment options are available: medical therapy, percutaneous drainage, surgery, and "watch-and-wait" approach. Albendazole (ABZ) is the drug of choice for CE treatment, its bioavailability being superior to that of mebendazole (MBZ), the first benzimidazole found to have in vivo activity against CE [
      • Schantz P.M.
      • Van den Bossche H.
      • Eckert J
      Chemotherapy for larval echinococcosis in animals and humans: report of a workshop.
      ]. ABZ is orally administered at a total daily dose of 10–15 mg/kg [
      • Horton R.J
      Albendazole in treatment of human cystic echinococcosis: 12 years of experience.
      ]. When ABZ is unavailable, MBZ can be used at a total daily dose of 40–50 mg/kg. WHO-IWGE currently recommends a 3–6-month continuous regimen of ABZ without interruption [
      • Tamarozzi F.
      • Horton J.
      • Muhtarov M.
      • et al.
      A case for adoption of continuous albendazole treatment regimen for human echinococcal infections.
      ]. ABZ alone can be considered for cysts C1 and CE3a smaller than 6 cm but is less effective for cysts C1 and CE3a larger than this size and for cysts CE2 and CE3b [
      • Stojkovic M.
      • Zwahlen M.
      • Teggi A.
      • et al.
      Treatment response of cystic echinococcosis to benzimidazoles: a systematic review.
      ]. Elevation of liver function tests is the commonest adverse effect associated with these drugs [
      • Bradley M.
      • Horton J.
      Assessing the risk of benzimidazole therapy during pregnancy.
      ]. Praziquantel 40 mg/kg/week plus ABZ has a more effective scolicidal effect than ABZ monotherapy [
      • Cobo F.
      • Yarnoz C.
      • Sesma B.
      • et al.
      Albendazole plus praziquantel versus albendazole alone as a pre-operative treatment in intra-abdominal hydatisosis caused by Echinococcus granulosus.
      ]. Percutaneous techniques consist of puncture, aspiration, injection and re-aspiration (PAIR) of a scolicidal agent (ethanol or hypertonic saline) into the cyst. Cysto-biliary communications should be ruled out before the procedure which is effective in CE1 and CE3a cysts larger than 5 cm and is not effective in solid component (CE3b) or multilocular (CE2) cysts. PAIR should be performed in presence of a resuscitation team as the procedure may be complicated by the unpredictable and rare occurrence of anaphylactic shock [
      • Neumayr A.
      • Troia G.
      • de Bernardis C.
      • et al.
      Justified concern or exaggerated fear: the risk of anaphylaxis in percutaneous treatment of cystic echinococcosis-a systematic literature review.
      ]. For cysts >10 cm, PAIR is contraindicated due to the large amount of fluid to drain for obtaining a successful procedure. The surgical techniques are radical (en-bloc removal of parasitic cysts, including the pericystium) and conservative (removal of the endocyst leaving the pericyst in place) [
      • Vuitton D.A.
      • McManus D.P.
      • Rogan M.T.
      • Romig T.
      • Gottstein B.
      • Naidich A.
      • Tuxun T.
      • Wen H.
      • Menezes da Silva A.
      World Association of Echinococcosis
      International consensus on terminology to be used in the field of echinococcoses.
      ]. Conservative treatments are associated with lower mortality (1.2%) and both intraoperative (14.8%) and postoperative (19.4%) complications [
      • Al-Saeedi M.
      • Ramouz A.
      • Khajeh E.
      • El Rafidi A.
      • Ghamarnejad O.
      • Shafiei S.
      • Ali-Hasan-Al-Saegh S.
      • Probst P.
      • Stojkovic M.
      • Weber T.F.
      • Hoffmann K.
      • Mehrabi A
      Endocystectomy as a conservative surgical treatment for hepatic cystic echinococcosis: a systematic review with single-arm meta-analysis.
      ].
      PICO 17 - In patients with uncertain imaging diagnosis of parasitic cysts, are serological tests indicated to confirm the diagnosis?
      The diagnosis is based on the combination of clinical, instrumental, and serological criteria. Diagnosis is possible if there is a compatible clinical and epidemiological history and positive serology; probable if the clinical history and the instrumental and serology findings are positive; confirmed if there are protoscolices in the cyst fluid aspirated or components of the cyst at surgery [
      • Tamarozzi F.
      • Akhan O.
      • Cretu C.M.
      • Vutova K.
      • Fabiani M.
      • Orsten S.
      • Pezzotti P.
      • Popa G.L.
      • Velev V.
      • Siles-Lucas M.
      • Brunetti E.
      • Casulli A
      Epidemiological factors associated with human cystic echinococcosis: a semi-structured questionnaire from a large population-based ultrasound cross-sectional study in eastern Europe and Turkey.
      ]. The Western Blot method proved to be the serological test with the highest accuracy (sensitivity 83%, CI 72–91%; specificity 98%, CI 91–100%) [
      • Tamarozzi F.
      • Longoni S.S.
      • Vola A.
      • et al.
      Evaluation of nine commercial serological tests for the diagnosis of human hepatic cyst echinococcosis and the differential diagnosis with other focal liver lesions: a diagnostic accuracy study.
      ]. If Western Blot cannot be used in the first instance, the use of two first-level tests (e.g., ELISA and indirect hemagglutination), with the Western Blot confirmatory method in the event of a discordant or negative concordant result, proved to be an equally valid strategy [
      • Vola A.
      • Manciulli T.
      • De Silvestri A.
      • et al.
      Diagnostic performances of commercial ELISA, indirect hemagglutination, and western blot in differentiation of hepatic echinococcal and non-echinococcal lesions: a retrospective analysis of data from a single referral centre.
      ].
      Recommendation
      In patients with uncertain imaging diagnosis of parasitic cyst, we suggest serological tests for diagnostic confirmation. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 18 - In patients diagnosed with single or multiple parasitic cysts, should a therapeutic intervention be indicated?
      Complications of active cysts are frequent and include rupture, infection, and biliary fistula. Rupture occurs up to 35% of untreated active cysts, mostly in the biliary tree causing cholangitis and/or obstruction [
      • Marti-Bonmati L.
      • Menor Serrano F
      Complications of hepatic hydatid cysts: ultrasound, computed tomography, and magnetic resonance diagnosis.
      ,
      • Prousalidis J.
      • Kosmidis C.
      • Kapoutzis K.
      • et al.
      Intrabiliary rupture of hydatid cysts of the liver.
      . More rarely, rupture may occur in the peritoneum, causing anaphylactic shock or acute abdomen [
      • Karavias D.
      • Vagianos C.
      • Kakkos S.
      • et al.
      Peritoneal echinococcosis.
      ]. Bacterial super-infection was found in 7.3% of cases with possible further complications to septic shock and death [
      • García M.B.
      • Lledías J.P.
      • Pérez I.G.
      • et al.
      Primary super-infection of hydatid cyst-clinical setting and microbiology in 37 cases.
      ]. Biliary fistula is common and its frequency increases with size as cysts > 7.5 cm have 80% probability of being associated with this complication [
      • Rinaldi F.
      • Brunetti E.
      • Neumayr A.
      • et al.
      Cystic echinococcosis of the liver: a primer for hepatologists.
      ,
      • Collado-Aliaga J.
      • Romero-Alegría Á.
      • Alonso-Sardón M.
      • et al.
      Complications associated with initial clinical presentation of cystic echinococcosis: a 20-year cohort analysis.
      . Based on these data, an expert consensus recommends the treatment of active cysts [
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      • et al.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ].
      Recommendation
      In patients diagnosed with single or multiple parasitic cysts, staged CE1, CE2, CE3a and CE3b, we suggest a therapeutic intervention to avoid cyst growth and complications. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 19 - In patients with stage CE1 and CE3a parasitic cysts, does surgical treatment give better results than percutaneous treatment?
      A study randomized 50 patients with EC with predominant liquid component to PAIR or surgery (cystectomy). The two techniques were equally effective; however, patients treated with PAIR experienced fewer complications and required shorter hospital stay [
      • Khuroo M.S.
      • Wani N.A.
      • Javid G.
      • et al.
      Percutaneous drainage compared with surgery for hepatic hydatid cysts.
      ]. PAIR is less invasive than surgical treatment, and a success rate of 97% was reported in patients with stage CE1 and CE3a cysts. Mortality ranges from 0% to 1% and morbidity from 8.5% to 32% [
      • Ustünsöz B.
      • Akhan O.
      • Kamiloğlu M.A.
      • et al.
      Percutaneous treatment of hydatid cysts of the liver: long-term results.
      ,
      • Giorgio A.
      • de Stefano G.
      • Esposito V.
      • et al.
      Long-term results of percutaneous treatment of hydatid liver cysts: a single center 17 years experience.
      ,
      • Salama H.
      • Farid Abdel-Wahab M.
      • Strickland G.T
      Diagnosis and treatment of hepatic hydatid cysts with the aid of echo-guided percutaneous cyst puncture.
      ,
      • Filice C.
      • Brunetti E
      Use of PAIR in human cystic echinococcosis.
      ]. A prospective study demonstrated that perioperative adjuvant administration of ABZ reduces cyst recurrence [
      • Akhan O.
      • Yildiz A.E.
      • Akinci D.
      • et al.
      Is the adjuvant albendazole treatment really needed with PAIR in the management of liver hydatid cysts? A prospective, randomized trial with short-term follow-up results.
      ]. A recent systematic review showed that the results of PAIR are comparable to those of laparoscopic surgery in terms of efficacy and safety [
      • Sokouti M.
      • Sadeghi R.
      • Pashazadeh S.
      • et al.
      A systematic review and meta-analysis on the treatment of liver hydatid cyst using meta-MUMS tool: comparing PAIR and laparoscopic procedures.
      ]. WHO-IWGE experts suggest treating CE1 and CE3a cysts larger than 5 cm with PAIR while smaller cysts may be treated with medical therapy alone [
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      • et al.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ].
      Recommendation
      • a.
        In patients with stage CE1 and CE3a cysts larger than 5 cm, PAIR is preferred over surgical treatment. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      • b.
        In patients with stage CE1 and CE3a cysts smaller than 5 cm, we suggest medical treatment. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 20 – In patients with stage CE2 and CE3b cysts, does surgical treatment give better results than percutaneous treatment?
      Radical or conservative surgical treatments of hepatic cysts are associated with perioperative mortality between 0% and 6.5%, morbidity between 12% and 84%, and recurrence between 0% and 30% [
      • Filippou D.
      • Tselepis D.
      • Filippou G.
      • et al.
      Advances in liver echinococcosis: diagnosis and treatment.
      ,
      • El Malki H.O.
      • El Mejdoubi Y.
      • Souadka A.
      • et al.
      Predictive factors of deep abdominal complications after operation for hydatid cyst of the liver: 15 years of experience with 672 patients.
      ,
      • Kapan M.
      • Kapan S.
      • Goksoy E.
      • et al.
      Postoperative recurrence in hepatic hydatid disease.
      ,
      • Daradkeh S.
      • El-Muhtaseb H.
      • Farah G.
      • et al.
      Predictors of morbidity and mortality in the surgical management of hydatid cyst of the liver.
      ,
      • Al-Saeedi M.
      • Khajeh E.
      • Hoffmann K.
      • et al.
      Standardized endocystectomy technique for surgical treatment of uncomplicated hepatic cystic echinococcosis.
      ]. Among percutaneous treatments, the "modified catheterization technique” (MoCat) was first described in 2007 to treat CE2 and CE3b cysts [
      • Akhan O.
      • Gumus B.
      • Akinci D.
      • et al.
      Diagnosis and percutaneous treatment of soft-tissue hydatid cysts.
      ]. This technique can kill parasites, evacuate the endocyst and the matrix, and obliterate the residual cavity. Encouraging results have been reported in small series [
      • Schipper H.G.
      • Lameris J.S.
      • van Delden O.M.
      • et al.
      Percutaneous evacuation (PEVAC) of multivesicular echinococcal cysts with or without cystobiliary fistulas which contain non-drainable material: first results of a modified PAIR method.
      ,
      • Gabal A.M.
      • Khawaja F.I.
      • Mohammad G.A
      Modified PAIR technique for percutaneous treatment of high risk hydatid cysts.
      ,
      • Akhan O.
      • Salik A.E.
      • Ciftci T.
      • et al.
      Comparison of long-term results of percutaneous treatment techniques for hepatic cystic echinococcosis types 2 and 3b.
      ]. However, the MoCat technique is performed only in few centers and there are no studies comparing it to surgery that remains the standard treatment for stage CE2 and CE3b cysts.
      Recommendation
      In patients with stage CE2 and CE3b parasitic cysts, surgical treatment is preferred over percutaneous or medical therapy. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 21 - In patients with stage CE4 and CE5 asymptomatic/inactive parasitic cysts, does surgical or percutaneous treatment give better results than follow-up?
      There are no randomized studies comparing treatment with "watch-and-wait" in CE4 and CE5 cysts. Retrospective studies show a negligible risk of reactivation and complications in patients undergoing US follow-up. In one study, 38 patients with 47 CE4 and CE5 liver cysts were followed with US at 6–12 months intervals (median follow-up 51.9 months); in 97.4% of patients the cysts remained inactive [
      • Piccoli L.
      • Tamarozzi F.
      • Cattaneo F.
      • et al.
      Long-term sonographic and serological follow-up of inactive echinococcal cysts of the liver: hints for a "watch-and-wait" approach.
      ]. An update of the same study included 53 patients with 66 cysts; 41.5% of patients completed a 5-year follow-up and only one case of reactivation was observed [
      • Lissandrin R.
      • Tamarozzi F.
      • Mariconti M.
      • et al.
      Watch and wait approach for inactive echinococcal cyst of the liver: an update.
      ]. Overlapping results were shown in a prospective cohort of 30 patients with 46 inactive cysts. No reactivation was reported in a median follow-up of 5.4 years [
      • Stojkovic M.
      • Rosenberger K.D.
      • Steudle F.
      • et al.
      Watch and wait management of inactive cystic echinococcosis - does the path to inactivity matter - analysis of a prospective patient cohort.
      ].
      Recommendation
      In patients with asymptomatic/inactive parasitic cysts in stages CE4 and CE5, follow-up is preferred over treatment. Very low quality of evidence (D); strength of recommendation 2 (conditional)
      PICO 22 - In patients with single or multiple complicated parasitic cysts, is surgical treatment indicated?
      The most frequent complication is rupture in the biliary tree causing abdominal pain, jaundice, cholangitis, or septic shock. Surgery is the choice treatment and a systematic review showed that the best treatment is common bile duct exploration with intraoperative cholangiography and choledochoscopy. When the biliary tract is cleared of cystic content, Kehr-tube positioning is sufficient [
      • Dziri C.
      • Haouet K.
      • Fingerhut A.
      • et al.
      Management of cystic echinococcosis complications and dissemination: where is the evidence?.
      ]. A retrospective study showed that the morbidity following this technique was significantly lower than that after choledocho-duodenostomy (18% vs. 40%) [
      • Elbir O.
      • Gundogdu H.
      • Caglikulekci M.
      • et al.
      Surgical treatment of intrabiliary rupture of hydatid cysts of liver: comparison of choledochoduodenostomy with T-tube drainage.
      ]. When possible, surgical removal of cysts should also be considered. In a study of 35 complicated cysts, treated with removal of cystic and pericystic tissue and simultaneous treatment of the fistulous tract, postoperative morbidity was 23% without mortality and recurrence (follow-up > 8 years) [
      • Chautems R.
      • Bühler L.H.
      • Gold B.
      • et al.
      Surgical management and long-term outcome of complicated liver hydatid cysts caused by Echinococcus granulosus.
      ].
      Recommendation
      In patients with single or multiple complicated parasitic cysts, we suggest surgical treatment. Low quality of evidence (C); strength of recommendation 2 (conditional)

      Declaration of Competing Interest

      None declared.

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