Nonparasitic hepatic cysts consist of a heterogeneous group of disorders, which differ in etiology, prevalence, and manifestations. With improving diagnostic techniques, hepatic cysts are becoming more common. Recent advancements in minimally invasive technology created a new Era in the management of hepatic cystic disease. Herein, the most current recommendations for management of noninfectious hepatic cysts are described, thereby discussing differential diagnosis, new therapeutic modalities and outcomes.

Nonparasitic hepatic cysts consist of a heterogeneous group of disorders, which differ in etiology, prevalence, and manifestations, from simple cysts to neoplastic lesions. Differential diagnoses of hepatic cysts include: infectious (hydatid cyst, amebic and pyogenic abscesses), and noninfectious [simple cyst, polycystic liver disease (PCLD), cystadenoma, cystadenocarcinoma and hepatocarcinoma (HCC), cholangiocarcinoma, intrahepatic pseudocysts secondary to pancreatitis, liver hematomas, biliomas, ciliated hepatic foregut cyst] (Table 1). Sometimes, these lesions are not easily differentiated at initial presentation or by imaging studies, and management can become challenging. With improving diagnostic techniques and minimally invasive technology, the management of hepatic cystic disease continues to evolve. We, herein, describe the most current management of noninfectious hepatic cysts, thereby discussing differential diagnosis, treatment options and outcomes.

Simple hepatic cyst is a biliary malformation, which does not have communication with the intrahepatic biliary tree. Most cysts measure less than 3 cm and are asymptomatic. Microscopically, they are lined by a single layer of cuboid or columnar epithelial cells, resembling biliary epithelial cells. Its origin is derived from aberrant bile ducts that have lost communication with the biliary tree, and continue to secrete intraluminal fluid[1]. The incidence is larger in adults older than 50 years, with female to male ratio 1.5:1, and prevalence is around 18% in adult population[2]. In the majority of patients, liver function tests are within the normal range. Asymptomatic single liver cysts, even when large, do not require treatment or surveillance. Ultrasound (US) is the best imaging modality for recognizing simple cysts, which appear as a circular or oval, anechoic lesion with smooth borders and acoustic posterior enhancement and without septations[3]. Further imaging studies, including computed tomography (CT), are not routinely required and show non-septated, round and water-dense lesions. In symptomatic patients requiring intervention, either sclerotherapy or surgical fenestration, hydatid cyst should be ruled out in all cases before the operation by serology, and by the patient history of recent travel to endemic areas. In lesions suspicious for cystadenoma, the recommended therapy is surgical resection, as this lesion has malignant potential[4-8].

Sclerotherapy consists of the destruction of the epithelial lining of the inner surface of the wall to disrupt the intracystic fluid secretion[9-11]. Under general anesthesia, drainage catheter is introduced by Seldinger technique and under ultrasound guidance, followed by injection of water-soluble contrast to rule out communication with adjacent bile duct or peritoneal cavity. Sclerosing agents include ethanol, minocycline hydrochloride and ethanolamine oleate[12]. The amount of alcohol injection is limited (100-200 mL) due to the risk of alcohol intoxication, and retention lasts usually between 120-240 min[13]. The solution is then aspirated before the catheter is removed. The size of the cyst does not play a role in the amount of sclerosing agent given because after cyst collapses, sclerosant will come into contact with the cyst inner wall. Contraindications of sclerotherapy include intracystic bleeding and fistula between the cyst and biliary tree or peritoneum. The optimal efficacy may be seen up to a year after sclerotherapy, and symptomatic recurrence rate is around 20% after 4 mo[14]. Due to high recurrence rates, management by aspiration followed by sclerotherapy should be reserved for those patients who are not eligible for surgery and general anesthesia[15].

Surgical fenestration, also known as unroofing, consists of an excision of the roof of the cyst to provide communication between the cyst and the peritoneal cavity. Limitations include cysts involving segments VII or VIII, which have higher recurrence rates due to anatomical position. Hemorrhage and biliary injury are, although rare, possible complications[16]. There is no associated mortality and morbidity ranges from 0%-15%, with reoperation rates at 9%[17]. There is no randomized prospective study to date comparing fenestration and sclerotherapy. In most centers, sclerotherapy is attempted first as a noninvasive option, and laparoscopic fenestration is usually indicated in refractory cases. Laparoscopy has become the procedure of choice for deroofing because is associated with significant reduction in hospital stay, postoperative pain and morbidity, and decreased blood loss[15,18]. To avoid recurrence, it is necessary to resect as much of the wall as possible to prevent closure of the remnant wall and reaccumulation of cyst fluid. However, complete resection of the cyst is not necessary and is associated with higher complication rates. Transposition of omental patch to the cyst bed has been advocated as a means of diminishing recurrence, especially in segments VII and VIII, where early adhesion of the cyst wall to either the diaphragm or abdominal wall may lead to refilling, however this still need to be confirmed by controlled studies[19].

PCLD is a genetic disease responsible for the development of multiple hepatic cysts. It presents in two forms, with or without autosomal dominant polycystic kidney disease (ADPKD)[20]. Both have an autosomal dominant transmission and similar clinical presentation. PCLD associated with ADPKD is linked with mutations in the PKD1 (short arm of chromosome 16, encoding polycystin-1) or PKD2 gene (chromosome 4, encoding polycystin-2), whereas isolated PCLD is associated with heterozygous mutation in PRKC-SH or SEC63 genes[21-26]. Overall prevalence is the same in gender, but female population is associated with more severe liver disease[27]. Pregnancy, multiparity, and use of steroids further increase the risk for severe hepatic cystic disease[28].

In most patients, cysts are small and asymptomatic; when present, symptoms are related mainly to the volume of enlarged liver rather than the volume of a specific cyst, and include abdominal distension, dyspnea, pain and early satiety[29]. US shows multiple, fluid-filled, round or oval cysts with sharp margins. Cysts do not show contrast enhancement, and it may be extremely difficult to identify vascular and biliary structures adjacent to the cysts. CT scan shows fluid attenuation with no contrast enhancement, and magnetic resonance imaging (MRI) demonstrates hyperintense on T2-weighted and hypointense on T1-weighted images. Gigot’s classification[30] is used for staging based on CT findings: type I, less than 10 large cysts; type II, diffuse involvement of liver parenchyma, but with remaining large areas of noncystic liver parenchyma; and type III, massive, diffuse involvement of liver parenchyma with only a few areas of normal tissue between cysts. Complications are uncommon and include bleeding, rupture and infection of cysts[31]. The most severe complication is bacterial infection, especially those under dialysis for ADPKD or in immunosuppressed patients after renal transplantation[32-37]. This is usually managed with aspiration and drainage, and antibiotics. Cholestasis secondary to compression of adjacent biliary duct also may ensue, as well as portal hypertension, resulting from portal or hepatic vein compression[38]. The incidence of concurrent cerebral aneurysms is 8%, whereas mitral valve prolapse occurs in 25% in those with PCLD associated with ADPKD[39].

Most current therapies are invasive and consist of surgical removal or emptying of cysts aiming at decompression and reduction of the liver size. Medical management has been proposed in advanced PCLD with diffuse disease[40,41]. The efficacy of conservative management is still under investigation. Two recent randomized controlled trials have demonstrated that lanreotide, a long-acting somatostatin analogue, was associated with a limited reduction of liver volume in both types of PCLD, measured by CT or MRI as a primary endpoint[42-46]. Liver volume decreased by 2.9% in the lanreotide group, but increased by 1.6% in the placebo group[41]. Sclerotherapy and laparoscopic fenestration showed ineffective in the management of PCLD[47]. Current surgical options include: open fenestration, liver resection, or liver transplantation (Figure 1). Transcatheter embolization has been recently proposed, targeting at decreasing arterial supply to the cyst. Although improvement of symptoms and significant reduction of liver size were observed in most patients, the limited experience in such technically demanding procedure still pose limitation to widespread use[48].

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Figure 1 Treatment algorithm for management of noninfectious hepatic cysts (most common etiologies). 1: Although laparoscopic fenestration is considered the best therapeutic approach for management of symptomatic simple cysts, sclerotherapy is still performed as initial management of these lesions in some centers. PCLD: Polycystic liver disease.

Partial liver resection associated with fenestration of the remnant liver has been historically proposed and, although highly successful is some patients, it is associated with high morbidity and mortality rates, and its indications are becoming more selective. Liver transplantation is the only curative modality, and is the only option in patients with anticipated limited efficacy by liver resection[49-51] (Figure 1).

The appropriate surgical option may be defined based on Gigot’s classification; in type I, which corresponds only 10% of cases, laparoscopic fenestration is recommended as first option; in type II, open fenestration is usually implemented; and type III is a contraindication to fenestration and requires resection or liver transplantation in symptomatic cases. If liver transplantation is anticipated, prior fenestration or resection should be avoided to decrease the risk of transplantation[52-56].

Caroli’s disease is a rare congenital disorder characterized by multiple segmental intrahepatic cystic dilatations, firstly described in 1958 by Caroli et al[57]. It has an autosomal recessive inheritance linked to mutation in PKHD1 gene, leading to persistent embryonic bile ducts at different levels of the intrahepatic biliary tree. It is also classified as type V choledochal cyst by Todani classification[58]. As opposed to PCLD, cystic lesions are irregular in shape, fusiform or saccular, and communicate with biliary tree. Patients usually present with recurrent episodes of cholangitis of unknown source, intrahepatic lithiasis and cholelithiasis[59-62]. In the presence of congenital hepatic fibrosis and portal hypertension, it is often termed Caroli’s syndrome[63,64]. US shows intrahepatic cystic anechoic areas in which fibrovascular bundles, stones and linear bridging or septum may be present[65]. The gold standard for diagnosis is direct visualization of the biliary tree, either endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous trans-hepatic cholangiography (PTC)[66]. Magnetic resonance cholangiopancreatography (MRCP) is an emerging modality for diagnosis of Caroli’s disease[67-69]. It has several advantages: noninvasive, readily available, and ability to visualize the entire biliary tract[70]. The characteristic appearance on MRCP is the “string of beads” pattern of the ectatic intrahepatic bile ducts. Most common complications of Caroli’s disease include cholangitis, sepsis, choledocholithiasis and hepatic abscess. At advanced stages, it may cause hepatic fibrosis with increased risks for cholangiocarcinoma and liver failure[71].

Management consists of treatment of acute cholangitis and control of sepsis with broad-spectrum antibiotics, ursodeoxycolic acid for hepatolithiasis, and palliative biliary drainage, either via PTC or ERCP with or without sphincterotomy. Patients with frequent cholangitis should undergo endoscopic surveillance every 6 to 12 mo[72]. Surgical options include partial liver resection for segmental or unilobar involvement[73], or liver transplantation, which is the only curative treatment[74]. Kassahun et al[75] described one of the largest experience with patients undergoing liver resection with or without biliodigestive anastomosis for unilobar disease with 84% of patients remained asymptomatic over 4 years follow-up period. Liver transplantation should be offered early in cases of recurrent cholangitis and suspicious for early malignant transformation of the biliary tract. The European transplant registry reported patient survival around 76% at 5 years after transplantation[76]. In diffuse disease and deemed to liver transplantation, bypass procedures, either choledochojejunostomy or Roux-en-Y hepaticojejunostomy may help palliate symptoms and increase survival.

Hepatic cystadenoma is a rare benign tumor of unknown etiology, and accounts for 5% of hepatic cystic lesions. Most lesions arise within the intrahepatic bile ducts and occur more commonly in females older than 40 years of age. It may present incidentally or if large, patients may present with jaundice and cholangitis for adjacent biliary compression[77]. Cystadenoma should be considered in any patient presenting with recurrent liver cysts after fenestration. Diagnostic imaging studies include a multiloculated lesion with internal septations, thickened and irregular wall, mural nodules and papillary projections, calcifications and wall enhancements[78]. Preoperative planning with direct visualization of biliary anatomy is necessary in most cases with ERCP or PTC, which confirm biliary tree communication[79-81]. The role of MRCP for preoperative imaging still needs to be defined[81]. It is challenging to distinguish the lesions from hepatic cystadenocarcinomas based on current diagnostic studies[82]. Irregular wall enhancement and the presence of papillary projections should increase suspicion for biliary cystadenocarcinoma[83]. Abnormal serum markers, such as CA 19-9 levels and carcinoembryonic antigen, may favor malignant transformation, although this is a variable finding. The current treatment modality is open or laparoscopic liver resection due to the risk of malignancy in all suspected cystadenomas[84-86] (Figure 1). Frozen sections are not reliable at evaluating these lesions and definitely excluding cystadenocarcinoma. Clear margins are advised due to the risk for synchronous carcinoma or foci of carcinoma in situ.

Biliary cystadenocarcinoma is a rare cystic neoplasm of unknown etiology, usually arising intrahepatic or, less frequently, in the extrahepatic bile ducts, and account for 0.41% of hepatic neoplasias[87]. The majority of these tumors are slow growing, and at the time of presentation, tumor is large with mean diameter at 12 cm, causing abdominal pain, intermittent jaundice, weight loss and ascites[88]. Current imaging studies are unable to confirm cystadenocarcinomas, however suggestive morphological findings may include: multilocular cyst mass with mural nodules at the periphery, and coarse calcifications. MRI further characterizes the content of the different locules not as serous fluid, but as a complex collection with proteinaceous material and hemorrhagic debris[89-91]. Preoperative fine-needle aspiration or needle biopsy is contraindicated due to the risk of fluid spilling into abdominal cavity and development of peritoneal carcinomatosis. Overall prognosis is better than HCC or cholangiocarcinoma with 5 years survival rate at 57% after resection, compared with 40% in HCC, and 22% in cholangiocarcinoma[92]. The only treatment option is formal hepatic resection which has acceptable recurrence rates (10%)[91,93] (Figure 1). In metastatic disease (20%), chemo- and/or radio-therapy have been advocated with doxorubicin and 5-FU, however results are yet limited[94].

Although uncommon, HCC and cholangiocarcinoma may occasionally be cystic, especially in rapidly growing tumors. Giant hemangiomas may rarely present as partly cystic, which corresponds to noncirculating areas, and kinetic of contrast enhancement is typical. Intrahepatic pseudocyst secondary from acute pancreatitis is extremely rare with less than 20 cases reported[95]. It may be seen in the left lobe along the lesser omentum, or in the right lobe along the portal vein. Pancreatic MRI may be useful to identify rupture of the pancreatic duct[1]. Liver hematomas may present as cystic lesions in CT scan or US after liver surgery or trauma, especially after clots liquefy at a later phase. They are spontaneously echogenic on US, hyperdense on CT scan, hyperintense on T1-weighted and hypointense on T2-weighted MRI sequences. Bilomas are cystic lesions surrounded by a fibrous capsule that can occur adjacent to the liver parenchyma secondary from traumatic, iatrogenic or spontaneous lesions.

Cystic hepatic metastases are rare, arising mostly from neuroendocrine, tumors, sarcoma, melanomas or pancreatic cystadenocarcinomas. The presence of increased peripheral vascularization and multiple lesions should rise suspicious for this rare lesion.

Peribiliary cysts arise from cystic enlargement of peribiliary glands, mostly occurring in cirrhotic patients with portal hypertension or after liver transplantation. The cysts are located along common bile duct or within portal tracts, and are usually small and asymptomatic[96].

Ciliated hepatic foregut cysts are benign lesions that have been described in most gastrointestinal organs, including the liver[97,98]. They form where the foregut extends during the embryonic period, and are extremely rare. It consists of four-layer border; pseudostratified, ciliated columnar epithelium covering a subepithelial connective tissue, smooth muscle bundles, and an outer fibrous capsule, and usually located in the anterior surface of the liver. Most cases are asymptomatic and incidentally found during abdominal imaging studies, however patients may present with epigastric or right upper quadrant pain[99]. Imaging characteristics include: predominance in segment IV, small size, subcapsular location. Two thirds are hypoechoic on US, hypodense on CT, and highly hyperintense on T2-weighted images on MRI[97,100].

Biliary hamartomas (also known as von Meyenburg complexes) are asymptomatic lesions, usually discovered incidentally during liver surgery[101]. They may be associated with Caroli’s disease, PCLD and congenital hepatic fibrosis, and identification is clinically important because may be misdiagnosed as liver metastasis[102].

Most hepatic cysts are benign, small, and asymptomatic lesions that are diagnosed incidentally and require no intervention, whereas large, symptomatic or neoplastic cysts need further treatment. Symptomatic simple cyst should be managed with laparoscopic unroofing; PCLD can be managed, in most cases, with partial resection; or liver transplantation for advanced multiloculated disease. Biliary cystadenomas and cystadenocarcinomas require complete resection with clear margins. With recent advancements in diagnostic studies, hepatic cysts are becoming more common and better understanding of risk factors; long-term outcomes and further development of current therapeutic modalities are needed.