New Energy Devices in the Treatment of Cystic Echinococcosis

Abstract

Treatment of cystic echinococcosis of the liver still remains a debatable subject. The method of choice should aim for the total elimination of the parasite with minimum morbidity and mortality. Different approaches have been proposed. Medical treatment as a monotherapy has been abandoned due to the high chances of recurrence and is mostly used as an adjuvant to surgery or minimally invasive methods. Surgical methods are divided into conservative ones, which include cystectomy and partial pericystectomy, and radical ones, total pericystectomy and hepatectomy. Radical procedures are correlated with lower complication and recurrence rates and, therefore, should be attempted when indications are present. On the other hand, conservative surgery can be the first option in endemic areas, performed by non-specialized general surgeons. The development of laparoscopic techniques made their use a possible alternative approach in selected cases. The use of percutaneous treatments is also quite widespread due to their minimally invasive nature. New energy devices seem to play a significant role in the treatment of cystic echinococcosis, although more studies are needed to establish their efficacy. Observation without intervention is an option for inactive uncomplicated cysts.

1. Introduction

When the question of how we are going to treat the echinococcus cyst exists, there is no specific answer. Once cystic echinococcosis is diagnosed it requires an immediate treatment, as the cysts usually grow and cause complications. The treatment of choice should aim for the total elimination of the parasite and prevention of recurrences, with minimum morbidity and mortality.

Treatment options of Cystic echinococcosis of the liver include: (1) surgical treatment (open or laparoscopic), (2) minimally invasive approaches, (3) endoscopic/interventional treatment, (4) medical treatment, or (5) observation without intervention (“watch-and-wait”) [1].

The appropriate treatment is determined by the characteristics of the disease, regarding the cyst number, size and location, the patient’s current health state and the availability of medical staff. An algorithm for the possible treatment according to the stage of cysts is shown in Table 1. The stage of the cyst is defined by the US classification that WHO-IWGE suggests, that takes into account the size, location and presence/absence of complications and classifies the cysts into three relevant groups: active (CE1 and 2), transitional (CE3) and inactive (CE4 and 5) (Table 2). Percutaneous treatments (PT) and antiparasitic treatment with benzimidazoles (BMZ), such as Albendazole, represent alternatives to surgery [1, 2].

Type	Description	First Option Treatment	Alternative
CE1 Active	Simple cyst often full of hydatid sand. Visible cyst wall. Fertile.	Only ABZ(6 m); Surgical treatment +ABZ(1–6 m); Surgical treatment +ABZ(1–6 m)	PAIR+ABZ(1 m); PAIR+ABZ(1 m); MoCaT+ABZ (1 m)
CE2 Active	Multiple or multi-loculated cysts. May appear honeycomb like with daughter cysts. Fertile.	Only ABZ(6 m); Surgical treatment +ABZ(1–6 m); Surgical treatment +ABZ(1–6 m)	MoCaT+ABZ (1 m); MoCaT+ABZ (1 m); MoCaT+ABZ (1 m)
CE3 Transition	Degenerating cyst but still contain viable protoscolices. Often see floating membranes in fluid filled cysts.	Only ABZ(6 m); Surgical treatment +ABZ(1–6 m); Surgical treatment+ABZ (1–6 m)	MoCaT+ABZ (1 m); MoCaT+ABZ (1 m); MoCaT+ABZ (1 m)
CE4 Inactive	Degeneration is advanced. Cysts may be calcified. Not likely to be fertile. Heterogeneous appearance with few or no daughter cysts.	Watch and wait	Watch and wait
CE5 Inactive	Often calcified. Usually infertile.	Watch and wait	Watch and wait
Complicated cyst	Any diameter. Complicated, no matter what stage	Surgical Treatment(+/− interventional endoscopy in case of rupture into the biliary tract) + ABZ(6 m)	Surgical Treatment in case of rupture. Percutaneous drainage in case of infection+ ABZ(1 m)

Table 1.

Therapy protocol for cystic echinococcosis by WHO [2].

Type	Description
I	Pure fluid collection (the cyst is similar to simple liver cysts) (CE1)
II	Fluid collection with a detached membrane, “honeycomb”(CE2)
III	Fluid collection with multiple septa and/or daughter cysts (CE3)
IV	Hyperechoic with high internal echoes (CE4)
V	Cyst with reflecting, calcified, thick wall(CE5)

Table 2.

Classification of cystic echinococcosis by Gharbi et al. [3] and WHO [2].

2. Surgical treatment

Surgery is the first choice for large CE2-CE3b cysts with multiple daughter cysts, single superficial cysts, complicated or infected cysts and cysts communicating with the biliary tree. Some contraindications for surgery are the inactive asymptomatic cysts or the very small cysts, difficult to access cysts because of their location and the general condition of the patient that does not allow them to undergo surgery. The classic types of surgery procedures differ in the approach of pericyst, i.e. the capsule that surrounds the cyst. In simple cystectomy, the pericyst is not resected by the surgeons and is dealt with in second time. The procedures that include resection of the pericyst are the partial pericystectomy, total pericystectomy and hepatectomy. Cystectomy and partial pericystectomy have been introduced as conservative surgery options, whereas total pericystectomy and hepatectomy are considered radical operations [4].

Simple cystectomy is a conservative safe and fast procedure but has high rates of postoperative morbidity and recurrence. In this procedure, only the cyst’s content is removed and the pericyst is retained. The remaining cavity is then treated with methods such as external drainage with a drain tube, bipolar drainage of the cavity and the main bile duct, padding, omentoplasty, drainage of the cavity by anastomosis with the stomach/jejunum or pericysto-biliar drainage. Omentoplasty seems to be the best possible surgical alternative for the radical treatment of hepatic cystic echinococcosis, due to reduced complications compared to external drainage. The method of external tube drainage is recommended for infected cysts. Biliary drainage procedure can also be added when the cysts are accompanied with intrabiliary rupture [5].

Partial pericystectomy, in which the cyst is opened, sterilized and its content is removed, with partial resection of the pericyst, is a procedure especially suited for endemic areas where the operations are performed by general surgeons and no special equipment is required. Subtotal pericystectomy is an approach similar to partial pericystectomy, with the difference that the surgeon leaves the pericystic areas closed to vessels and bile ducts untouched, to avoid complications such as biliary leakage and hemorrhage [6].

In total pericystectomy, where the whole pericyst is resected, two methods can be used; the closed total pericystectomy, in which the cyst is removed without opening, and the open total pericystectomy, where sterilization with protoscolicidal agents take place first, evacuation the contents of the cyst and then removal of the pericystic tissue. The open method is preferred when the cyst has a thin wall and there is a risk of rupture a major vascular structure with the closed cyst method. Consequently, in total pericystectomy, where the opening of the cyst is avoided, the recurrence of the disease is minimized [7].

Liver resections that have been proposed for the treatment of cystic echinococcosis are segmentectomy and left or right lobe hepatectomy. Remnant liver tissue’s function is a thing to take under consideration, as it has been proven that in cases where a large hepatic parenchymal part needs to be removed or echinococcosis-related hepatic cirrhosis occurs as a complication, liver transplantation is then necessary [1]. Nevertheless, hepatectomy may be performed when conservative methods have failed, the cyst compresses the healthy liver tissue and impair a lobe or segment, and interrupt with the biliary tree or cystobiliary fistulas in draining zones are present [6].

In hepatectomy and total pericystectomy, the complete resection of the closed cysts with a fairly wide safety margin is achieved. However, these radical interventions involve an increased risk of postoperative complications, such as rupture into the bile ducts and the creation of biliary fistulas, which are quite important given the benign nature of the disease. The question of whether is preferable to perform these approaches rather than conservative surgery stays controversial nowadays. A recent meta-analysis showed that overall postoperative complications are lower compared to conservative surgery and no statistically significant differences were detected in terms of mortality risk and the duration of hospital stay between the two methods [8].

Inactivation of the parasite must precede the opening of the cyst cavity regardless the type of surgery that is going to follow. At present, 20% hypertonic saline is recommended, which should be in contact with the germinal layer for at least 15 minutes. Alternative options are ethyl alcohol, hydrogen peroxide or Albendazole, but these agents are accompanied with a higher risk of complications. The isolation of the cyst from the rest of the peritoneal cavity must also be ensured. This can happen by wrapping the adjacent areas with dressings soaked in anthelmintic substances or by applying adherent cones to the cyst using the icing technique or suction. Benzimidazole (BMZ) agent is usually used after surgery to reduce the risk of anaphylaxis and secondary CE [4].

2.1 Surgical treatment of complicated cystic echinococcosis

The most common complication of hepatic cystic echinococcosis is rupture into the biliary tree and it appears in 10–25% of patients. The clinical symptoms of cystobiliary communications are obstructive jaundice, abdominal pain, fever, nausea and vomiting. If an intrabiliary rupture is found perioperatively, cholangiography and endoscopic removal of any residual debris in the common bile duct can be performed. Alternatively, if cystobiliary communications are suspected after the operation, common bile duct can be explored with a T-tube drainage or a following choledochoduodenostomy. Cystobiliary fistulas are defined whenever bile leakage is continued up to 10 days. Treatment essentials for fistulas are endoscopic intervention with sphincterotomy, stent insertion, or nasobiliary tube drainage.

Peritoneal perforation can occur in approximately 10–16% of patients after surgery or percutaneous treatment. It presents with similar symptoms as intrabiliary rupture, including allergic reactions and anaphylactic shock. A confirmed diagnosis with U/S or CT is necessary to build the treatment strategy, which can be radical or conservative surgery [1, 4].

2.2 Laparoscopic technique

Laparoscopic surgery, which is also a minimally invasive technique, can reach well results in the treatment of cystic echinococcosis. Especially, cysts located peripherally and anteriorly can be resected successfully with a laparoscopic operation in uncomplicated patients. However, posterior, deep or calcified cysts, and cysts located close to the inferior vena cava cannot be selected for this procedure. Specifically, the contraindications for laparoscopic surgery are patients CE5 without clinical symptoms, those who have liver function grade C in Child–Pugh classification with no potential aspect to downstage, intolerance of laparoscopic surgery based on patient’s current health state, deep intraparenchymal or inaccessible cysts and relapsed CE, multiple cysts with diffuse distribution in liver, extrahepatic metastasis, dense adhesions surrounding the CE cysts difficult to separate and cysts with thickness of external capsule wall less than 3 mm [9].

The benefits of laparoscopic surgery include reduced post-operative pain, faster exit of the hospital and great cosmetic results. During the procedure, visualization of the surgical field on the monitor allows detailed exploration of the cystic cavity in a larger image and makes possible the detection and removal of germinal layer’s remnants [10].

Both conservative and radical surgery approaches can be performed with laparoscopic technique. Considering the fact that laparoscopic partial pericystectomy has higher rates of recurrence and postoperative complications, this approach is advised when a history of multiple surgeries is present or the space between external layer and liver parenchyma is limited. Total pericystectomy seems to be a great option in selected patients, as it can succeed the total elimination of the disease leaving a small wound. Therefore, total pericystectomy can be considered as the treatment of choice when laparoscopic surgery is about to be performed [11].

With laparoscopic surgery, short-term recurrence rates are 0–9%, while the recurrence of the disease after an open surgery is 0–30%. Postoperative morbidity rates in laparoscopic procedures are 8–25% and mortality 0%, whereas morbidity and mortality with open methods are 12–63% and 0–3% each. On the other hand, the risk of complications, especially leakage to the biliary tree, is more common to occur in laparoscopic surgeries due to peritoneal spillage that is less predictable with this technique [6].

3. Minimally invasive/interventional treatment

Percutaneous treatments of hepatic CE can aim at the destruction of the germinal layer (PAIR) or the evacuation of the entire endocyst (Modified Catheterization Techniques).

PAIR (Puncture, Aspiration, Injection, Re-aspiration) is a relatively recent and minimally invasive therapeutic option that consists of four steps: percutaneous puncture of the cyst using U/S guidance, aspiration of the cyst fluid, injection of a protoscolicidal agent (e.g., 95% ethanol or 20% NaCl) and re-aspiration of the fluid. This method has reduced risk compared with surgery, improved efficacy of chemotherapy given before and after the procedure (probably because of an increased penetration of antihelminthic drugs into cysts re-filling with hydatid fluid), reduced hospitalization time and less cost.

Indications for PAIR include non-echoic lesion ≥5 cm in diameter (CE1m and l), cysts with daughter cysts (CE2), and/or with detachment of membranes (CE3), multiple or infected cysts and patients who refuse surgery. Contraindications for PAIR are non-cooperative patients and inaccessible location of the cyst, inactive or calcified lesion and cysts communicating with the biliary tree. The most serious risks of PAIR involve allergic reactions, secondary echinococcosis and chemical cholangitis. The possibility of secondary echinococcosis can be minimized by concurrent treatment with benzimidazole [12].

It is good to be noticed that PAIR procedure is showing a higher cure rate, lower complication rate, and lower mortality compared with laparoscopic surgery. Superiority of the laparoscopic approach is visible only in terms of recurrence rates [13].

If PAIR cannot be used, as in cases of rupture to the biliary tree or the presence of a giant cyst, then the modified catheterization technique (MoCat) is suggested. In this procedure, a catheter is inserted into the cystic cavity and is followed by continuous injections and aspirations of isotonic saline solution, until the total removal of endocyst and daughter cysts is achieved and the daily output falls down to 10–15 ml/24 hours [1].

A modified PAIR method, that is suitable for patients with multivesicular cysts containing non-drainable content, is percutaneous evacuation (PEVAC). This technique is characterized by U/S guided cyst puncture, injection and re-aspiration of isotonic saline due to a large bore catheter, use of scolecidals if no cystobiliary communication is present or external drainage of cystobiliary fistulas combined with endoprosthesis or sphincterotomy and catheter removal when and the daily output is less than 10 ml. In case of a univesicular cyst with a cystobiliary fistula, PEVAC is more safe compared to PAIR because a possible damage to the biliary tree or blood vessels by scolecidals can be avoided [14].

4. New energy devices

4.1 Radiofrequency ablation

Radiofrequency ablation (RFA) was first introduced to the field of hepatobiliary as an alternative, more innovative technique that can be used as percutaneous treatment of solid liver tumors. In this method, a needle conducting high-frequency electrical energy is inserted into the cyst’s cavity and cause heat-mediated necrosis of the surrounding tissue. The heat inside the cyst leads to denaturation of the proteins and can succeed the distraction of its germinal layer [15].

There have been described series of attempts to use RFA as a scolidial agent in the ablation setting in percutaneous treatment approaches for cystic echinococcosis or intraoperatively as a surgery tool. Thermal ablation of the germinal layer was first introduced by Brunetti et al. [16]; the scientists reported that U/S guided RFA in a percutaneous ablation setting for the treatment of complex cysts is safer and simpler than large-bore catheters and the need to use some additional methods did not came up. Later on, more surgical teams managed to achieve good short-term results including RFA to their percutaneous procedures [17, 18]. However, at that time, the lack of sufficient data on the subsequent course of the patients does not allow safe conclusions regarding the effectiveness of the method in preventing recurrences of the cystic echinococcosis. Intraoperative use of U/S-guided RFA appears to be a safe and very promising approach that can be performed in liver resections. This technique is related with minimal blood loss and allows maximum liver parenchyma preservation. U/S guided RF pericystectomy is indicated especially in cases of cysts located away from the liver hilum [19].

Great advantages are associated with this method, such as the fact that the use of scolidial agents with injections and aspirations, large catheters or other evacuations steps is not necessary. However, this technique comes with limitations, due to the high costs of the equipment that is required and the need for high skilled surgeons. Also, RFA cannot be used in cases of superficial or peritoneal cysts and cysts attached to hollow and vascular structures [15]. While the recurrence rates seems to be low, prospective studies are initial to show if RFA has a critical superiority in cystic echinococcosis treatment compared to other approaches [20].

4.2 High-intensity focused ultrasound

High-intensity focused ultrasound (HIFU) is a non-invasive, image guided method that can be provably used in urology cases and certain tumors [21]. This procedure is characterized by the application of high-energy waves to a specific area causing cell death, cavitation and necrosis of a small part of tissue. The damage to protoscolices, that requires the presence of high temperatures, is achieved due to conversion of acoustic beams into heat and cavitation effects that are gained with gaseous micro-bubbles formation. Therefore, HIFU is effective in both inhibition of the growth of protoscolices and their development to germinal layer [22].

Effectiveness of HIFU has been proven to be enhanced with use of a superabsorbent polymer and ultrasound contrast agent, especially when they are used in combination [23].

The advantages of HIFU lie in its non-invasiveness type, which means that possible complications of invasive methods such as infections, allergic reactions and rupture to surrounding tissues can be avoided. Some significant constraints are the expense of the equipment, the need for general anesthesia and the weakness of its use on all cyst stages. Nevertheless, there is a need of further evaluation of HIFU for the treatment of cystic echinococcosis [15].

5. Medical treatment

Chemotherapy with antiparasitic drugs for the treatment of echinococcal cyst of the liver was initially used in patients who had contraindications for surgical treatment. Through the bibliographic review of this method’s results the last decades and the introduction of new surgical techniques the exclusive use of chemotherapy has been limited. Given the fact that is not possible to ensure the complete disappearance of daughter cysts through medication and, therefore, the cyst with regenerate, this approach has a low chance of cure and high rates of recurrence (3–30%) [4].

Nowadays, medical treatment is primary used as an adjuvant therapy to surgery or minimally invasive techniques. Anthelminthic drugs that can be used are the benzimidazoles (BMZ) albendazole and mebendazole, and praziquantel. is used to prevent recurrence and secondary hydatidosis. Albendazole (ABZ) is the drug of choice for the treatment of hepatic CE at the average dose of 10–15 mg/kg/day. Praziquantel is used with ABZ for combined treatment that reaches more efficacy than ABZ alone [24]. Mebendazole can be used alternatively when albendazole is not tolerated by the patient, in the dose of 40–50 mg/kg per day, higher than ABZ due to its poor absorption but with a comparable efficiency. The duration of medical treatment with these agents is indicated to be 4–30 days prior to the surgical operation and continued for at least 1 month with albendazole or 3 months with mebendazole [25]. Pre- and postoperative use of albendazole decreases the viability of cysts at the time of surgery and reduces the rates of recurrence and secondary hydatosis [26].

Medical treatment with a BMZ can be used alone in patients who have disseminated disease, in those who have comorbid disease, and who have small (<5 cm) CE1 and CE3 cysts in the liver and lungs. The recommended duration of therapy is 6 months with ABZ, while MBZ treatment requires a longer period of time [25].

Most common side effects of BMZ are nausea, hepatotoxicity, neutropenia and occasionally alopecia. Therefore, patients should be regularly checked with liver function tests and leukocyte counts. Medical treatment with BMZ must not be encouraged in cases of pregnancy, chronic hepatic diseases and bone marrow depression [12].

6. Watch-and-wait

Uncomplicated cysts do not require any treatment. CE4 and CE5 cysts should not be treated, until their parasitic nature has been proven. In these cases, long-term follow-up of patients with U/S imaging maybe is enough until a change in the behavior of the cyst is observed. A 5-year follow-up in cysts that inactivated naturally is recommended, while cysts that became inactive due to interventions require closer observation due to higher recurrence rates (50% in 18 months) and reconsideration of the best approach after a 5-year follow-up [27].

7. Future directions

New energy devices such as RFA and HIFU have significantly enhanced surgical outcomes in certain patients. The great results of the reported evidence prove the necessity of turning attention to these emerging technologies and the need to implement them in treatment strategies and real-life clinical practice. More studies are expected to validate the mentioned results and reveal their superiority to classic approaches.

8. Conclusion

Cystic echinococcosis of the liver is a condition that can easily become complicated and, therefore, careful treatment is necessary. Among the various treatment options, surgical methods seem to have prevailed over the years, due to the definitive cure they can provide. However, the surgical approach is not free of complications and requires an experienced coordinated medical staff. The evolution of percutaneous methods has made their use a good alternative option, but also includes several risks. There is strong evidence that new energy devices can clear the field of treatment choices. Radiofrequency ablation and high-intensity focused ultrasound are both very promising techniques and the results of more studies are expected in order to demonstrate their efficacy in the treatment of cystic echinococcosis.