Sonography and Clinical Outcome of Viable Hydatid Liver Cysts Treated With Double Percutaneous Aspiration and Ethanol Injection as First-Line Therapy: Efficacy and Long-Term Follow-Up
Abstract
OBJECTIVE. The objective of our study was to report our 19-year experience with sonography and the clinical outcome of viable hydatid liver cysts treated with double percutaneous aspiration and ethanol injection as first-line therapy.
CONCLUSION. Viable hydatid liver cysts can be safely and successfully managed with double percutaneous aspiration and ethanol injection as first-line-therapy.
Introduction
Hydatid disease, due to the larval form of a tapeworm Echinococcus granulosus, is a parasitic disease endemic in the Mediterranean area, Middle East, South America, India, Northern China, and Australia [1]. Moreover, considering the increased worldwide travel and tourism, it can be found anywhere in the developed countries [1]. Cystic hydatid disease usually affects the liver (50–70%) and less frequently lung, spleen, kidney, bone, and brain [2]. Liver hydatidosis can cause dissemination or anaphylaxis after a cyst ruptures into the peritoneum or biliary tract. Infection of the cyst can facilitate the development of liver abscesses and mechanic local complications, such as mass effect on bile ducts and vessels that can induce cholestasis, portal hypertension, and Budd-Chiari syndrome [2]. In addition, the presence of daughter cysts in an older cyst represents a significant risk of recurrence after surgery [1]. Treatment of hydatid liver cyst has to be considered mandatory in symptomatic cysts and recommended in viable cysts because of the risk of severe complications [3].
In the last two decades, minimally invasive sonographically guided percutaneous approaches have been developed [4]. Percutaneous aspiration, injection, and reaspiration with scolicidal agents have been widely used with excellent results [4, 5]. The main complication of percutaneous aspiration, injection, and reaspiration is anaphylaxis because of spillage of the echinococci. However, many reports showed that anaphylaxis is a rare event when the procedure is performed by an expert operator [6, 7].
In 1992, we presented a modified technique of percutaneous aspiration, injection, and reaspiration, called double percutaneous aspiration and ethanol injection, characterized by no reaspiration of the injected ethanol [8]. Double percutaneous aspiration and ethanol injection showed high efficacy on unilocular hydatid liver cysts in terms of disappearance of the cysts and few side effects [8]. The purpose of this nonrandomized prospective study was to evaluate whether double percutaneous aspiration and ethanol injection also is effective in patients with previously untreated viable multivesicular hydatid liver cysts. We report the results in a large series of previously untreated patients with viable univesicular and multivesicular hydatid liver cysts treated with double percutaneous aspiration and ethanol injection as first-line therapy and suggest some clinical implications in the management of these patients.
Subjects and Methods
Patients
From January 1988 to January 2007, 143 patients (100 males and 43 females; age range, 13–80 years) with 210 viable hydatid liver cysts (diameter: range, 2.8–20.0 cm; mean, 4.8 cm) underwent double percutaneous aspiration and ethanol injection. There were 152 univesicular (113 patients) and 58 multivesicular (30 patients) cysts with World Health Organization (WHO) 2001 classification [9] of CL, CE1, CE3, and CE2. CL is an active unilocular cyst with uniform anechoic content and no clearly visible cystic wall; CE1 is an active unilocular simple cyst with uniform anechoic content and cystic wall well visible; CE2 is an active multivesicular, multiseptated cyst with cystic wall well visible; CE3 is an active unilocular cyst with an inner floating detached membrane. These sonographic patterns are shown in Figures 1A, 1B, 1C, 1D, 1E, 1F, and 1G. Patients with inactive cysts with WHO 2001 classification CE4 (with pseudotumor, solid sonographic pattern) or CE5 (cyst with calcified wall) [9] were not treated.
We have previously reported on 66 patients with 93 univesicular hydatid liver cysts and 13 patients with 26 multivesicular hydatid liver cysts who underwent treatment with double percutaneous aspiration and ethanol injection [10]. The current study includes 47 additional patients with 59 additional univesicular hydatid liver cysts and 17 additional patients with 32 additional multivesicular hydatid liver cysts.
Double percutaneous aspiration and ethanol injection was offered as an alternative to surgery to the first 14 patients [8] and afterward as first-line therapy to the remaining patients. Informed written consent was obtained from all patients included in the study and our institutional ethical committee approved the double percutaneous aspiration and ethanol injection protocol from 1992.
Before double percutaneous aspiration and ethanol injection, diagnosis of echinococcosis was made on the basis of the presence of antibodies against Echinococcus granulosus using indirect hemagglutination assay (IHA) or enzyme-linked immunosorbent assay (ELISA) at a titer of ≥ 1:128 (in all cases of unilocular cyst) or sonography-specific patterns (CE2 or CE3) as mentioned previously. In 138 (96.5%) of 143 patients, double percutaneous aspiration and ethanol injection represented the first therapeutic approach; the remaining five patients (3.5%) of 143 with five (3.3%) of 152 univesicular viable (CL or CE1) cysts had postsurgical cystic disease recurrence in a distant liver segment from the treated segment. There were 28 (19.6%) symptomatic patients. Eighteen (12.6%) of 143 patients had right upper quadrant pain associated with a palpable mass, and 10 (7%) of 143 had jaundice with sonographic dilatation of intrahepatic bile ducts. No patient had extrahepatic disease.
Double Percutaneous Aspiration and Ethanol Injection Technique
Double percutaneous aspiration and ethanol injection was carried out as previously described [8, 10]. Under sonographic guidance, the cyst was punctured using a 22-, 20-, or 18-gauge needle (Ecojekt, HS) according to the cystic volume. After aspirating as much fluid as possible, 95% sterile ethanol was injected into the cyst and left in situ to replace 50–60% of the amount drained. At least 1 cm of liver parenchyma was interposed between the liver surface and cystic wall, when possible. In case of a subcapsular location, the needle was directly inserted into the cyst. Immediately after the aspiration of cystic fluid, a parasitologist searched for viable scolices with direct fresh microscopic examination and staining with 0.1% neutral red. To exclude the presence of a biliary fistula, the bilirubin level in the aspirated fluid was determined by a semiquantitative method (Combur-Test, Roche Diagnostics) within a few seconds before alcohol injection. When multiple cysts were present in the same patient, they were treated in the same session.
Mebendazole (3 g/d in the first 10 cases) or albendazole (800 mg/d in the remaining cases) was administered 3 days before and 3 weeks after double percutaneous aspiration and ethanol injection to all patients except two (one pregnant woman and one patient with chronic liver disease). Double percutaneous aspiration and ethanol injection was always performed with an anesthesiologist present. General anesthesia without endotracheal intubation (using atropine, 0.5 mg IV; induction with propofol, 1.0–1.5 mg/kg IV; maintenance with propofol, 9.0–12.0 mg/kg/h plus fentanyl citrate, 50 mg IV) was used routinely after July 2000 because of anaphylaxis in one patient.
Follow-Up
After double percutaneous aspiration and ethanol injection, all patients underwent clinical, laboratory, and sonography examinations every month for the first 3 months and every 6 months thereafter. Sonography was performed to control the efficacy of double percutaneous aspiration and ethanol injection in terms of disappearance of the cysts with reconstitution of liver parenchyma, decreased fluid component and pseudotumor, solid appearance, or decreased volume of the cyst. The reappearance of single or multiple pure liquid cysts with well-defined walls within a previously completely solid treated cyst was considered to be local recurrence after double percutaneous aspiration and ethanol injection, and the relapsed cyst was treated again with double percutaneous aspiration and ethanol injection. IHA or ELISA titers were determined monthly during the first 6 months and then twice a year. Chest radiography was scheduled every 6 months to exclude lung localization, and a total-body CT was scheduled every 2 years to exclude peritoneal and extraparenchymal localizations. We recommended performing CT rather than sonography, taking into account the major specificity of CT in identifying peritoneal and extraparenchymal localizations.
Statistical Analysis
The time of healing (disappearance, solidification, or small fluid appearance) of cysts ≤ 5 cm and > 5 cm was calculated by using the Kaplan-Meier method and the difference was determined by log-rank test. Results were expressed as hazard ratio with corresponding 95% CI and p values. Data processing and analysis were performed with SAS version 8.2 (Statistical Analysis Systems).
Results
Double Percutaneous Aspiration and Ethanol Injection Procedure
The initial double percutaneous aspiration and ethanol injection procedure was attempted on 143 patients with 210 hydatid liver cysts, but it was completed in 141 (98.6%) of those patients (see Complications section). Therefore, 111 patients with 150 univesicular hydatid liver cysts and 30 patients with 58 multivesicular hydatid liver cysts were treated (Fig. 2).
One course of double percutaneous aspiration and ethanol injection was performed in 126 (89.4%) of 141 patients: 110 patients had 149 univesicular hydatid liver cysts and 16 had 24 multivesicular hydatid liver cysts. Two courses of double percutaneous aspiration and ethanol injection were performed in one patient (0.7%) with one very large univesicular hydatid liver cyst. Three and four courses of double percutaneous aspiration and ethanol injection were performed in the remaining 14 (9.9%) patients with 34 multivesicular hydatid liver cysts: six patients underwent three courses of double percutaneous aspiration and ethanol injection and eight underwent four courses of double percutaneous aspiration and ethanol injection (Fig. 2). After one-time double percutaneous aspiration and ethanol injection, the healing rate was 99.3% in 110 patients with 149 univesicular hydatid liver cysts and 41.4% in 16 patients with 24 multivesicular hydatid liver cysts.
Three hundred eighty-seven sonographically guided percutaneous needle punctures were performed, and viability of the cysts was confirmed in all cases by the presence of viable scolices in the aspirated fluid. The ethanol injected ranged between 12 and 250 mL per session. The double percutaneous aspiration and ethanol injection procedure lasted between 15 and 45 minutes.
In symptomatic patients, the loss of cyst tension caused immediate disappearance of abdominal mass, and jaundice disappeared within 4–17 days. The mean hospital stay was 2.9 days (range, 2–7 days).
Sonographic Follow-Up
The follow-up ranged from 12 to 228 months (mean, 54 months). Forty-six (32.6%) of 141 patients were followed from 1 to 4 years, whereas the remaining 59 (41.8%) and 36 patients (25.5%) were followed from 5 to 8 years and from 9 to 19 years, respectively.
One hundred thirty-five (64.9%) of 208 viable hydatid liver cysts disappeared with reconstitution of liver parenchyma; 41 (19.7%) of 208 showed a solid pattern, i.e., inactive cyst with heterogeneous hypoechoic or hyperechoic degenerative contents without daughter cysts. Therefore, the sonographic pattern changed from active (CL, CE1, CE2, or CE3) to inactive (CE4, in our series). In the remaining 32 (15.2%) of 208 cysts, there was a residual small liquid component with 80% decreased volume compared with the pretreatment size (Fig. 3). These 32 latter cysts underwent percutaneous aspiration, and no viable scolices were found in the aspirated fluid.
Both solid and liquid inactive cysts showed decreased volume, ranging from 50% to 80% compared with the baseline volume (Figs. 4A, 4B, and 4C). There was a clear relationship between the baseline volume of the cysts and the time taken to obtain the stable posttreatment sonographic pattern; the smaller the cysts, the shorter the healing time. The difference between the time of healing (i.e., disappearance, solidification, or small liquid component sonographic appearance) of the cysts ≤ 5 cm (range, 20–70 days; mean, 43 ± 14 [SD] days) compared with cysts > 5 cm (range, 3–24 months; mean, 12 ± 8 months) was statistically significant (p = 0.001; odds ratio = 2.33; 95% CI, 1.71–3.351).
Local recurrences were observed in 15 (10.6%) of 141 patients. Of these 15 patients, 14 had multivesicular cysts (13 patients with 18 multivesicular cysts [> 2 daughter cysts] and one patient with one bilocular cyst) and the remaining patient had one large univesicular cyst. The patient with a bilocular cyst showed a solid hyperechoic pattern after double percutaneous aspiration and ethanol injection that remained unmodified for 2 years. Two years later this patient presented with fever, jaundice, and dilatation of the biliary tree on sonography. Diagnosis of ruptured cyst in the biliary tract was made. The patient was treated with ERCP. No viable scolices were found on parasitologic examination, and, after 2 months, sonography showed the reconstitution of the liver parenchyma. The patient with a large univesicular cyst had undergone double percutaneous aspiration and ethanol injection for a single, 6-cm unilocular pure liquid cyst, which healed with a solid hypoechoic pattern and decreased in volume (Figs. 5A and 5B). Five years later, sonography showed a liquid pattern relapse (large pure liquid cyst reappeared within the previous successfully treated cyst), and the patient was successfully treated again with double percutaneous aspiration and ethanol injection (see Double Percutaneous Aspiration and Ethanol Injection Procedure section).
As of this writing, only one of these 15 relapsed patients who underwent multiple double percutaneous aspiration and ethanol injection has shown the persistence of three daughter cysts within a previously solid cyst on sonography. This patient had a large multivesicular cyst before double percutaneous aspiration and ethanol injection. In the remaining 14 patients, a solid pattern with decreased volume (50% of the baseline volume) was observed on sonography. Therefore, the healing rate in the 15 patients undergoing multiple double percutaneous aspiration and ethanol injection was 93.3% (14 of 15 patients). No recurrences in another area of the liver or extrahepatic recurrences have been observed during follow-up.
Complications
Major complications were observed in five patients (3.5%): one patient died from anaphylaxis (mortality rate, 0.7%); two developed pyogenic liver abscesses from Escherichia coli in two cysts 15 and 60 days after double percutaneous aspiration and ethanol injection. In both cases, the abscesses were drained percutaneously and reconstitution of liver parenchyma was observed on sonography 1 month later. One patient showed intracystic bleeding during the first needle aspiration, and the procedure was immediately stopped. In the remaining patient, a biliary fistula (Combur-Test was positive) was diagnosed because bile-stained fluid was collected during the second aspiration. Given the patient's stable clinical condition, no other diagnostic or therapeutic procedure was carried out and the second double percutaneous aspiration and ethanol injection was postponed until 6 months after spontaneous closure of the fistula. The overall morbidity rate was 4.9%. Minor complications were recorded in three patients (2.1%): abdominal pain in two and nausea and vomiting in one.
Discussion
In a review by Dziri et al. [11], the authors sought to provide evidence-based answers to the following questions: Should chemotherapy be used alone or in association with surgery? What is the best surgical technique? When is the percutaneous aspiration, injection, and reaspiration technique indicated? The results showed that chemotherapy is not the ideal treatment for uncomplicated hydatid liver cyst when used alone, and the level of evidence was too low to help in choosing between radical or conservative treatment. Percutaneous drainage plus albendazole proved to be safe and effective in selected patients [4, 11]. Smego and Sebanego [12], in a meta-analysis of 769 hydatid liver cyst patients who underwent percutaneous aspiration, injection, and reaspiration plus albendazole and 952 matched control subjects who underwent surgery, found that percutaneous aspiration, injection, and reaspiration plus chemotherapy is associated with greater clinical and parasitological efficacy; lower rates of morbidity, mortality, and disease recurrence; and shorter hospital stays [12].
Our nonrandomized prospective study showed that double percutaneous aspiration and ethanol injection is highly effective with very few side effects (3.5%) and a low mortality rate (0.7%) in patients with previously untreated viable hydatid liver cysts. Regarding the disappearance of the cysts with reconstitution of liver parenchyma on sonography, we reported a high percentage (64.9%) of cysts disappeared. These results are not reported in other series with long-term follow-up [5–13]. These results confirm our previous 11-year experience [10] on approximately half the number of viable hydatid liver cysts (119) as are reported in this study (208). In the series of Ustünsöz and coworkers [13], only 1% of patients treated with percutaneous aspiration, injection, and reaspiration showed disappearance of the cysts. In addition, in the experience of Etlik et al. [14], none of the percutaneous aspiration, injection, and reaspiration–treated cysts disappeared. In our experience, the mortality rate was 0.7% (one patient). In surgical series with long follow-up periods, the mortality range was from 0.3% to 7%, operative time was 175 minutes; and hospital stays ranged from 6 days in laparoscopic series to 15 days in open radical surgery [15].
In a large series [16] of 510 hydatid liver cysts in the 355 patients, the percutaneous aspiration, injection, and reaspiration recurrence rate was 3.5% compared with the recurrence rates of 16.2% and 3.3% for open and laparoscopic surgery, respectively. In surgical series, the range of surgical complications ranged from 6% to 47% [17–20], and these results are not similar to our percentages. Moreover, our results in patients without disappearance of the cysts on sonography showed a reduction of 50–80% of cystic baseline volume with a 19.7% solid pattern and a 15.5% fluid inactive pattern. On the basis of these considerations, we propose a parasitologic cure for an initial success rate of 99% in viable hydatid liver cysts treated with double percutaneous aspiration and ethanol injection as first-line therapy; this is true for the short and middle term and was maintained even in the long term in more than 80% of cases. The high rate of parasitologic cure continues over time, with a very low incidence (10.6%) of local recurrence, which can be retreated with another session of double percutaneous aspiration and ethanol injection. Therefore, these results strongly suggest double percutaneous aspiration and ethanol injection to be the first-line choice of therapy for hydatid liver cysts.
Clearly, our data would be even more relevant if compared with those obtained with percutaneous aspiration, injection, and reaspiration. In fact, our idea of modifying percutaneous aspiration, injection, and reaspiration into double percutaneous aspiration and ethanol injection took place because of the observation that there is still the possibility of finding viable protoscolices within hydatid liver cysts after percutaneous aspiration, injection, and reaspiration, as shown in our previous experience [8] and that of other investigators [21].
Finally, the time taken to attain the final sonographic pattern varied considerably. The time was short (within 70 days) when the cysts were small, whereas the largest cysts took longer, up to 2 years. Even in patients followed for more than 2 years, no changes over time—disappearance, solid inactive, or liquid inactive—were observed on sonography. Only one patient with a unilocular cyst showed an intracystic active relapse.
On the basis of our experience, we suggest some clinical implications in the management of viable hydatid liver cysts (Fig. 6). In patients with small univesicular (≤ 5 cm) viable hydatid liver cysts the follow-up should be performed every month for the first 3 months after double percutaneous aspiration and ethanol injection. Thereafter, once the final sonographic pattern is established, the follow-up can be based on sonography every 1 or 2 years. In patients with large (> 5 cm) univesicular viable hydatid liver cysts, because the reconstitution of liver parenchyma on sonography could be observed up to 2 years after double percutaneous aspiration and ethanol injection, the follow-up should be continued up to 2 years and afterward every 12–24 months. On the other hand, patients with viable multivesicular cysts should be strictly followed every 3 months for the first 3 years to recognize an early relapse and thereafter every 6 months. Finally, in patients with a local relapse (single or multiple), a new double percutaneous aspiration and ethanol injection can be performed.
Our results confirm that double percutaneous aspiration and ethanol injection is an effective and safe technique for previously untreated patients with viable univesicular and multivesicular hydatid liver cysts not only in the short term, but also in the long term. Double percutaneous aspiration and ethanol injection has a low cost, the hospital stay is very short, and the few cases of local recurrence can be retreated. Therefore, double percutaneous aspiration and ethanol injection can be adopted in developing and in Western countries, and we suggest performing this procedure as first-line treatment in patients with viable hydatid liver cysts.
Footnotes
Address correspondence to A. Giorgio ([email protected]).
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History
Submitted: July 10, 2008
Accepted: February 17, 2009
First published: November 23, 2012
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