Focal Therapy and Imaging in Prostate and Kidney Cancer: High-Intensity Focused Ultrasound Ablation of Small Renal Tumors

Abstract

The rising incidence of small, incidentally detected renal masses in elderly, infirm patients has raised interest in minimally invasive, energy ablative techniques. High-intensity focused ultrasound (HIFU) delivers ultrasonic energy, resulting in heat and tissue destruction in the targeted tissue at a selected depth. In contrast to radiofrequency ablation and cryoablation, HIFU does not require puncturing the tumor, avoiding the high risk of hemorrhage or tumor spillage. While the extracorporeal approach shows unsatisfactory results, laparoscopic HIFU appears to be a promising alternative treatment option. Problems with respiratory movement and interphases, as seen in extracorporeal HIFU, are avoided when the transducer is brought directly to the target by laparoscopic HIFU. Potential benefits of laparoscopic HIFU are decreased morbidity, shorter hospitalization and convalescence, and preservation of renal function. Nevertheless, further prospective studies have to be performed to define the oncological success of HIFU as an alternative to open and laparoscopic surgery in small renal masses.

Introduction

H igh-intensity focused ultrasound (HIFU) for the treatment of small renal masses (SRM) has gained enormous interest over the past years. This trend has been supported by the fact that an increasing number of SRM (<4 cm) are detected incidentally through the widespread use of abdominal computed tomography (CT) and ultrasonography.^1,2 Since the 1970s, the rate of incidental detection of small renal tumors of low stage and low metastatic potential has increased by 60%.³ For most of these small lesions the traditional open, radical nephrectomy has been replaced by nephron-sparing surgery. In solitary tumors less than 4 cm, nephron-sparing surgery has proven to provide recurrence-free and long-term survival rates similar to those observed after a radical surgical procedure.^4
–6 Technological advances have caused a further shift from the open approach to laparoscopy or other minimally invasive techniques. More recently, energy ablative techniques are progressively emerging as potential alternatives in selected patients.

HIFU relies on the same principles as conventional ultrasound. As ultrasound waves propagate through nonhomogenous media such as biologic tissue, some of the mechanical energy is converted to heat. If the waves are focused at a precisely defined location to achieve higher site intensity, heat sufficient for thermal damage can be achieved. Above a threshold of 60°C, protein denaturation occurs, resulting in cell destruction and coagulative necrosis.^7
–9 The induction of this thermal necrosis depends on several factors, including ultrasound frequency, exposure time, absorption coefficient, acoustic reflection and refraction, and perfusion rate in the targeted tissue. HIFU implies no risk of hemorrhage or tumor spillage and is considered the most minimally invasive technique among the ablative treatments.^10,11 HIFU can be used by a minimal (laparoscopic) or noninvasive (extracorporeal) approach. Possible advantages of HIFU treatment include decreased morbidity, anesthesia other than general, minimal or no skin incisions, reduced postoperative pain, shorter hospitalization, and preservation of renal function. However, HIFU for the treatment of SRM has to be considered an investigational technique and there are no standard recommendations for its application.

Extracorporeal HIFU

Clinical data on extracorporeal HIFU for the treatment of small renal tumors are limited. In a phase II study conducted at our institution, 16 renal tumors were treated with extracorporeal HIFU, 2 with curative intent and 14 were subsequently removed. At follow-up, tumor shrinkage was observed in 2 patients, but residual tumor was detected at histological examination of the targeted tumor zone in all 14 patients in whom the tumor was removed after HIFU.¹² Häcker et al observed similarly insufficient results, with no correlation between energy administered and lesion achieved.¹³ Overall, the extracorporeal approach appears to be challenging because of acoustic complexity of intervening structures and the mobility of the kidney. Study results showed unsatisfactory tumor destruction with a high rate of incomplete ablations. Another drawback of the percutaneous approach is the lack of reliable radiologic methods to control the treatment effects of HIFU in real time. Thus, extracorporeal HIFU should not be considered as an alternative in the management of renal tumors, and for the time being, attempts for extracorporeal HIFU treatment of renal masses are concluded.

Laparoscopic HIFU

The problems with target mobility and multiple acoustic interphases seen in the extracorporeal approach can be avoided if the transducer is brought directly to the target by laparoscopic HIFU. A laparoscopic HIFU probe (Misonix) has recently undergone phase I and II testing at our center.¹⁴ This ultrasound-image-guided device uses HIFU to cause thermal coagulative necrosis in the selected regions of tissue. A dual-function piezoelectric transducer is housed in a laparoscopic probe. The ultrasound mode allows accurate placement of the treatment focus as well as real-time imaging during the treatment. The device was exclusively designed for the treatment of kidney cancer in a sterile laparoscopic setting (Fig. 1). To provide direct contact with the targeted organ, the probe is inserted through an 18-mm trocar.

FIG. 1.

Intraoperative picture of the laparoscopic ultrasound probe (BK Medical) and laparoscopic high-intensity focused ultrasound probe (Misonix).

The HIFU energy is delivered by a truncated spherical shell transducer operating at 4.0 MHz. As the HIFU approach is still investigational, there are no standard protocols for its application in renal masses. Our protocol consists of two subsequent HIFU cycles as described earlier.¹⁴ During each cycle, HIFU delivery is briefly interrupted to obtain ultrasound images of the treatment zone, which are used to monitor treatment progress. If the tumor cannot be completely covered by a single treatment plan, multiple overlapping treatment plans must be used to completely ablate the entire tumor volume. As a result of the transducer's focal length, the maximum HIFU penetration depth is limited to approximately 35 mm. The maximum linear scanning extent of the transducer is 50 mm, and the maximum angular scanning extent of the transducer is 90°.

For laparoscopic HIFU, the surgical access is a standard transperitoneal approach with the patient in a 45° lateral decubitus position. The kidney has to be mobilized and cleared of fatty tissue, and the hilar structures should be dissected. Intraoperative renal Power Doppler ultrasonography with a 10-Hz laparoscopic ultrasound probe (BK Medical) provides additional information regarding the exact tumor location. Moreover, intraoperative Power Doppler examination can be used to screen for signs of vital tissue after the HIFU cycles. To gain access for the 18-mm HIFU probe, one of the four 12-mm ports has to be changed to a 25-mm port (Ethicon).

To evaluate the histological effects of laparoscopic HIFU on renal tumors, a clinical trial was conducted at our institution and initial data have already been published.¹⁴ A total of 15 patients were included in the study. In two patients a marker lesion was obtained before laparoscopic radical nephrectomy. Thirteen patients underwent laparoscopic HIFU in a curative intent, followed by laparoscopic partial nephrectomy in 12 patients. In one patient the tumor remained in situ, but was re-biopsied after 2 HIFU cycles. Tumor specimens were evaluated by extensive histopathological evaluation. Patients were followed up with serum creatinine, renal ultrasonography, and helical contrast enhanced CT scan or magnetic resonance imaging at 1, 3, and 6 months and every 6 months thereafter.

In 9 out of the 12 patients with solid renal masses (mean diameter, 2.2 cm; range, 1.1–4.0 cm), complete destruction of the tumors was achieved. Two of the tumors showed a 1–3-mm rim of viable tumor at the surface of the tumor immediately adjacent to the transducer. Obviously, the transducer was too close to obtain sufficient site intensity. This problem was subsequently avoided by keeping the transducer >7 mm from the tumor. Only one tumor showed central areas of vital tissue (i.e., skipping), corresponding to about 20% of the tumor volume. The histopathological evaluation demonstrated renal cell carcinoma at hematoxylin and eosin and nicotinamide adenine dinucleotide (NADH) staining. This incomplete ablation was considered to be a reperfusion injury. No intra- or postoperative complications or side effects were observed.

Discussion

HIFU can be effective at causing cell death in renal tumors and surrounding renal tissue.^15,16 Unfortunately, extracorporeal HIFU has shown to be unreliable with high rates of incomplete ablations and thus cannot be considered a suitable option for the treatment of renal masses. The key to good results is to approximate the energy source close to the target tissue. In our laparoscopic HIFU series, we did not experience any difficulties in applying the energy directly into the tumor area. To demonstrate oncological efficacy, laparoscopic radical nephrectomy or laparoscopic partial resection was performed after HIFU treatment. In only one patient the tumor remained in situ. Clinical follow-up CT scans up to 18 months after the HIFU treatment did not reveal any signs of tumor recurrence. This needs to be confirmed in long-term follow-up because multiple postoperative artifacts will make radiological interpretation difficult.

There are several weaknesses of the laparoscopic HIFU approach at this time. The probe tested for laparoscopic HIFU is still bulky, requiring an additional large access port. The kidney has to be completely mobilized and freed of any surrounding fat tissue to ensure adequate approximation of the renal tumor toward the probe, thereby making surgery more challenging and time consuming. Nevertheless, if laparoscopic HIFU treatment is performed without subsequent excision of the lesion, the potential complications of laparoscopic partial nephrectomy, including hemorrhage, warm ischemia, and urine leakage, can be avoided.^17,18

Comparing HIFU with other ablative techniques (Table 1), cryoablation seems to be a reliable technique with a 1.6% recurrence rate over 3 years of follow-up but only 1.8% complications. However, cryoablation requires an extensive technical back-up and represents an expensive surgical treatment. Radiofrequency ablation (RFA) appears to be unreliable in highly vascularized tumors with a high percentage of vital tumors to be found at histological work-up. Percutaneous techniques are less effective than laparoscopy, with recurrence rates ranging between 13% and 21% for cryoablation and 14% and 18% for RFA. Further, oncological follow-up relies solely on radiological measurements, frequently without histological verification, thus making percutaneous techniques unpredictable.

Table 1.

Comparison of Renal Ablative Techniques

	Technique
	High-intensity focused ultrasound	Radiofrequency ablation	Cryotherapy
Method of application	Laparoscopic or percutaneous	Laparoscopic or percutaneous	Laparoscopic or percutaneous
Real-time observation of ablated tissue	MRI or ultrasonography (limited)	Thermocouples	Ultrasonography, CT, MRI, or thermocouples
Necessity of puncturing the tumor	No	Yes	Yes
Risk of tumor spillage	No	Yes	Yes
Long-term data available	No	Yes	Yes

MRI = magnetic resonance imaging; CT = computed tomography.

A potential complication of ablative techniques is “skipping.” In our series there was one skip lesion. It remains unclear at this point why this skipping effect did occur, but most likely it represents a reperfusion injury. Tissue texture or vascularity has been reported to be an important factor influencing ablation success, particularly in RFA.^19
–21 These general rules also apply for laparoscopic HIFU. Another potential cause for skip lesions during HIFU could be incomplete probe contact with the tumor during the procedure. Removal of unnecessary tissue impedance borders and sufficient probe contact seem to be the most important point for successful ablation.

There is some concern in development of intraperitoneal drop metastasis and recurrent renal cell carcinoma after RFA or cryoablation because of potential tumor cell spillage at needle placement and during the ablation procedure. There have even been anecdotal reports of this potential complication.¹¹ We observed no port-site or intraperitoneal drop metastasis. In this respect, laparoscopic HIFU offers a significant potential benefit compared with other minimally invasive ablation techniques, as there is no need for tumor puncture with HIFU ablation. To clarify this issue, however, larger series and long-term data are warranted.

Limited information is available concerning the morbidity of HIFU, particularly on collateral damage to adjacent tissue or organs. In our series we did not encounter any HIFU-related intra- or postoperative complications.

The most important factors for HIFU treatment are imaging and guidance. Current HIFU systems utilize ultrasonography or magnetic resonance imaging for targeting and for monitoring the success of therapy. Unfortunately, the ability to monitor temperature with ultrasonography is not yet possible. Novel three-dimensional ultrasound systems represent the future, and refinements in HIFU devices as well as improvements in imaging techniques are expected to improve cancer control while reducing side effects and complications.

Conclusion

HIFU ablation is a feasible option for the treatment of SRM but remains an experimental approach now. Further research is warranted to clarify the oncological success and reliability of HIFU.

Footnotes

Disclosure Statement

The authors have nothing to disclose.

Abbreviations Used

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