Medical Policy

This document addresses the use of histotripsy to ablate tissue. Histotripsy is an incisionless non-thermal procedure that uses ultrasound to induce mechanical cavitation resulting in the transformation of targeted tissue into acellular debris. The mechanism of action for histotripsy differs from that for high intensity focused ultrasound (HIFU). In HIFU, the heat produced by high intensity focused ultrasound directly destroys tissue. The spread of this heat can damage adjacent tissue. Histotripsy creates microbubbles within tissue and it is the expansion and contraction of these bubbles that destroy cells. Histotripsy has been proposed as a treatment for malignant tissue, including liver lesions and renal cancer. This treatment has also been proposed for treatment of nonmalignant conditions such as benign prostatic hypertrophy (BPH).

Note: For other documents related to ultrasonic ablation techniques, please see the following:

• CG-MED-81 Ultrasound Ablation for Oncologic Indications
• MED.00057 MRI Guided High Intensity Focused Ultrasound Ablation for Non-Oncologic Indications

Medically Necessary:

Histotripsy is considered medically necessary when all of the following criteria (A, B, C, and D) are met:

1. Treatment is intended for destruction of liver tumors (primary or metastatic); and
2. There is a lack of other available therapies (locoregional therapies, chemotherapy, immunotherapy, targeted therapies) as evidenced by at least one of the following:
   1. Unresponsive to other therapies; or
   2. Relapse following other therapies; or
   3. Intolerant to other available therapies; or
   4. Thermal ablation is not viable due to tumor location (for example, proximity to vital structures or centrally located);
      and
3. Targeted tumor(s) diameter 3 centimeters (cm) or less; and
4. Three or fewer tumors will be treated.

Investigational and Not Medically Necessary:

Histotripsy is considered investigational and not medically necessary when the criteria above are not met.

Summary

Histotripsy is a nonthermal, ultrasound-based ablation technique that mechanically destroys tissue through acoustic cavitation, enabling precise, incisionless tumor treatment while sparing surrounding structures. It is considered medically necessary for individuals with up to three liver tumors ≤ 3 cm when other locoregional, systemic, or ablative therapies are not viable. Clinical evidence, including the HOPE4LIVER trial data, demonstrates high technical success, favorable safety, and local tumor control comparable to conventional ablation, with mostly mild, short-term adverse events.

Use of histotripsy for other indications, such as renal malignancy or BPH remains investigational. Early trials for renal tumors are ongoing, and current National Comprehensive Cancer Network (NCCN) and National Cancer Institute (NCI) guidelines do not endorse its use. Limited pilot studies in BPH show procedural feasibility but lack long-term or comparative data. While promising for nonthermal tissue destruction, further evidence is needed to establish safety, efficacy, and clinical benefit beyond hepatic applications.

Discussion

Histotripsy is a focal ablative therapy that destroys tissue by acoustic cavitation. It has been proposed as an alternative treatment of tumors. The proposed benefits of low-heat focal ablative therapy include avoidance of heat sink effects, which is theorized to allow histotripsy to be used in highly vascular areas (Hendricks-Wenger, 2021).

A phase I trial provided the initial safety and efficacy data regarding the use of histotripsy in individuals with hepatocellular carcinoma and hepatic metastasis (Vidal-Jove, 2022). In this study, 8 individuals with multifocal liver tumors were followed for 8 weeks post-procedure. There were no significant procedure-related events. The study focused on technical safety and did not provide follow-up data on cancer-related outcomes.

On October 6, 2023, the Edison^® System (HistoSonics^®, Ann Arbor, MI) received de novo marketing authorization from the FDA for the non-thermal destruction of liver tumors. On February 14, 2024, an updated Edison system was cleared for use in the non-invasive destruction of liver tumors. The authorization was based in part on the data from two single-arm, non-randomized prospective trials evaluating primary or metastatic liver tumors (NCT04572633, NCT04573881). Interim results have been published for one of those studies (Mendiratta-Lala, 2024). Participants will be followed for 5 years post-procedure (NCT04572633, NCT04573881). On October 1, 2024, the FDA approved the updated system for the treatment of liver tumors, as “substantially equivalent to the predicate device”.

Liver cancer

Mendiratta-Lala and colleagues (2024) published the results of a prospective multicenter, single arm trial (#HOPE4LIVER). Participants with up to 3 tumors smaller than 3 cm in size were treated with histotripsy. Participants included individuals with hepatocellular carcinoma (n=18) or with liver metastases from non-hepatocellular carcinomas (n=26). The co-primary endpoints address technical success, tumor treatment volume being greater than or equal to the targeted volume with complete tumor coverage, and safety, and the absence of procedure-related major complications through 30-day postoperative. All participants underwent a single session of histotripsy. Technical efficacy at 30 days was 83%. A total of 101 adverse events (AEs) were reported within 30 days postoperative, with 94 AEs (93.1%) categorized as nonserious. Of the 7 serious AEs, 3 were classified as primary safety end-point failures. These end-point failures included 1 case each of sepsis, pleuritic pain requiring inpatient care, and hepatic failure leading to death 37 days after the procedure. The remaining serious AEs were identified as splenic hematoma, melena, procedural pain, and progression of metastatic colorectal cancer. The study was limited to reporting early endpoints related to performance rather than clinical outcomes. The authors noted that the cohort in this study may not be typical of individuals who receive ablative treatment because many of them had stage IV metastatic disease. Longer-term 12-month data regarding safety and efficacy is being analyzed with plans to publish in the future.

Ziemlewicz (2025) reported on the 1-year clinical outcomes from the #HOPE4LIVER trial. Among 47 participants, the 1-year local tumor control rate was 63% by initial review and 90% after expert reassessment. This difference was explained as being due to a learning curve in interpreting the appearance of tissue disruption caused by the histotripsy treatment. One-year survival was 73% for hepatocellular carcinoma and 49% for metastatic disease. Most treatment zones showed progressive shrinkage (over 95% volume reduction), and nearly all adverse effects occurred within 30 days of treatment, primarily mild abdominal pain or fever. Only six serious device-related events were reported, and no delayed toxicities were found. Overall, histotripsy provided tumor control and safety outcomes comparable to current local liver therapies.

A multicenter retrospective case series (Wehrle, 2025) involving 295 individuals reported low complication rates (5.2% overall, 1.3% major). Nearly half of treated tumors were colorectal metastases and disease biology heterogeneity was not analyzed in the safety analysis. Although this study only reported 30-day safety outcomes and did not report long term tumor control effects, there were no device-related interventions, supporting early safety across diverse liver tumor types and locations. The 1.3 % major-event rate compares favorably to published 30-day major-complication rates of TACE (≈5-10 %), MWA/RFA (≈2-4 %), or hepatic resection (≈10-20 %). Industry involvement may have introduced a source of bias to this voluntary retrospective registry study.

A single-center cohort (Mabud, 2025) which included 26 individuals with 56 tumors described short-term safety and imaging findings after histotripsy used to treat liver metastases. Participants were ineligible for alternative NCCN-recommended locoregional therapy or were unfit for anesthesia. The imaging data were incomplete and heterogeneous: 1-month post-treatment tumor ablation zone volume and tumor long-axis dimension were reported for 21 participants while only 2 participants had corresponding 3-month data. There was no blinding or independent radiology review. Based on imaging, treatment was considered technically successful for 97% of the participants. Mild treatment-related adverse events were reported for 15% of the participants and 1 participant experienced bacteremia that was judged to be a major adverse event. Industry involvement represents a potential source of bias in this voluntary retrospective registry study with incomplete follow-up. The authors stated that “This study is limited by its retrospective nature, small heterogeneous cohort, single study center, and limited and non-standardized follow-up protocols, precluding robust conclusions regarding outcomes.”

Renal Cancer

Histotripsy is proposed for use to treat renal cancer; however, there are no published studies evaluating the use of histotripsy for this indication. There are two prospective, multi-center, single-arm clinical trials underway to evaluate the safety of effectiveness of the device in treating renal tumors. The CAIN trial (NCT05432232) and the pivotal #HOPE4KIDNEY trial (NCT05820087) are still recruiting participants and have a December 2024 estimated completion date. The preferred treatment of renal cancer is a partial or radical nephrectomy. For individuals with small tumors or for individuals who are not candidates for surgery, ablative therapy, such as RFA, cryoablation or stereotactic ablative body radiation therapy are considered standard alternative therapies NCI, Renal Cancer Treatment, 2024; NCCN, Kidney cancer V1.2026). Histotripsy is not mentioned as a potential treatment of renal tumors in any current guidelines.

BPH

Schuster and associates (2018) presented the results of a prospective cohort study in which 25 individuals with BPH were treated with histotripsy to relieve urinary obstruction. The primary study endpoint was safety as reflected by the rate of adverse events. There was 1 serious adverse event (urinary retention requiring catheterization for 8 days) and 26 other adverse events including catheter-related pain (n=8), dysuria (n=5), bladder spasm (n=5), urinary retention (n=3), minor anal abrasion (n=1), microhematuria (n=1), and local reaction at the catheter site (n=3). The authors describe this as a limited pilot study. Larger controlled studies with longer follow up are needed to evaluate outcomes of histotripsy compared to more established therapies for BPH.

Histotripsy is sometimes compared to HIFU, but the treatments are fundamentally different. HIFU is a thermal treatment that uses continuous or long bursts of ultrasound to induce heat resulting in tissue destruction. In contrast, histotripsy is a non-thermal treatment that employs “short ultrasound bursts with higher peak pressure amplitudes” to cause mechanical cavitation and tissue destruction (Verma, 2024). The treated tissue is liquefied and reabsorbed within 1-2 months post-treatment (Xu, 2024).

Histotripsy devices consist of a treatment head and probe linked to a touchscreen interface for real-time visualization and control. Tumor margins are mapped out and the probe generates bubble clouds in specific locations within the target area to confirm margins and determine the energy needed for cavitation. During ablation, overlapping histotripsy zones cover the tumor, with changes in ultrasound transmission observed. In histotripsy, focal volumes are stacked together to treat the target volume. This has the proposed benefit of sparing surrounding tissues, unlike thermal ablation. Robotic assistance can be incorporated to ensure precise positioning of the treatment arm over the tumor.

Histotripsy works differently in solid tissues compared to tissue-fluid interfaces. In solid tissue, histotripsy transforms tissue into a liquid, entirely removing cellular structures and creating clear acellular zones. In tissue-fluid interfaces, histotripsy erodes the tissue surface, causing the shedding of micrometer-sized cell debris and progressively thinning the tissue until it completely perforates. It is theorized that histotripsy may induce immune responses, potentially aiding in tumor regression and enhancing immunotherapy.

The benefits of non-thermal focal ablative therapy over other ablative therapies include tissue destruction in the targeted area and avoidance of heat sink effects which is theorized to allow histotripsy to be used in highly vascular areas (Hendricks-Wenger, 2021). Limitations of histotripsy include decreased effectiveness with increased target depths, potential risks in gas-filled organs, and a theoretical risk of metastasis due to tissue fragmentation (Verma, 2024).

Ablation: The destruction of a body part or tissue or its function. Ablation may be achieved by surgery, hormones, drugs, radiofrequency, heat, or other methods.

Cavitation: Creating cavities within the body by breaking down tissue at a cellular level. A number of methods can be used to facilitate tissue destruction including heat, radiation or mechanical.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the codes listed above when criteria are not met or for all other diagnoses, for the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Hendricks-Wenger A, Weber P, Simon A, et al. Histotripsy for the treatment of cholangiocarcinoma liver tumors: in vivo feasibility and ex vivo dosimetry study. IEEE Trans Ultrason Ferroelectr Freq Control. 2021; 68(9):2953-2964.
2. Jahangiri S, Yu F. Fundamentals and applications of focused ultrasound-assisted cancer immune checkpoint inhibition for solid tumors. Pharmaceutics. 2024; 16(3):411.
3. Khokhlova VA, Fowlkes JB, Roberts WW, et al. Histotripsy methods in mechanical disintegration of tissue: towards clinical applications. Int J Hyperthermia. 2015; 31(2):145-162.
4. Mabud TS, Vergara M, Du J, et al. Histotripsy of liver metastases: short-term safety and imaging findings. Cardiovasc Intervent Radiol. September 28, 2025. Online ahead of print.
5. Mendiratta-Lala M, Wiggermann P, Pech M, et al. The #HOPE4LIVER single-arm pivotal trial for histotripsy of primary and metastatic liver tumors. Radiology. 2024; 312(3):e233051.
6. Sandilos G, Butchy MV, Koneru M, et al. Histotripsy - hype or hope? Review of innovation and future implications. J Gastrointest Surg. 2024; 28(8):1370-1375.
7. Schuster TG, Wei JT, Hendlin K, et al. Histotripsy treatment of benign prostatic enlargement using the vortx rx system: initial human safety and efficacy outcomes. Urology. 2018; 114:184-187.
8. Verma Y, Perera Molligoda Arachchige AS. Advances in tumor management: harnessing the potential of histotripsy. Radiol Imaging Cancer. 2024; 6(3):e230159.
9. Vidal-Jove J, Serres X, Vlaisavljevich E, et al. First-in-man histotripsy of hepatic tumors: the THERESA trial, a feasibility study. Int J Hyperthermia. 2022; 39(1):1115-1123.
10. Wehrle CJ, Burns K, Ong E, et al. The first international experience with histotripsy: a safety analysis of 230 cases. J Gastrointest Surg. 2025; 29(4):102000.
11. Xu Z, Hall TL, Vlaisavljevich E, Lee FT Jr. Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperthermia. 2021; 38(1):561-575.
12. Xu Z, Khokhlova TD, Cho CS, Khokhlova VA. Histotripsy: a method for mechanical tissue ablation with ultrasound. Annu Rev Biomed Eng. 2024; 26(1):141-167.
13. Ziemlewicz TJ, Critchfield JJ, Mendiratta-Lala M, et al. The #HOPE4LIVER single-arm pivotal trial for histotripsy of primary and metastatic liver tumors: 1-year update of clinical outcomes. Ann Surg. April 9. 2025. Online ahead of print.

Government Agency, Medical Society, and Other Authoritative Publications:

1. HistoSonics, Inc. The HistoSonics Edison^™ System for treatment of pancreatic andenocarcinoma using histotripsy (GANNON). NLM Identifier: NCT06282809. Last updated on June 25, 2025. Available at: https://clinicaltrials.gov/study/NCT06282809?term=histosonics&aggFilters=status:rec%20act&rank=3. Accessed on October 8, 2025.
2. HistoSonics, Inc. The HistoSonics Edison^™ System for Treatment of Primary Solid Renal Tumors Using Histotripsy (#HOPE4KIDNEY) (#HOPE4KIDNEY). NLM Identifier: NCT05820087. Last updated on September 16, 2025. Available at: https://clinicaltrials.gov/study/NCT05820087?term=NCT05820087&limit=10&rank=1. Accessed on October 8, 2025.
3. HistoSonics, Inc. The HistoSonics Investigational System for treatment of primary solid renal tumors using histotripsy (CAIN). NLM Identifier: NCT05432232. Last updated on June 25, 2025. Available at: https://clinicaltrials.gov/study/NCT05432232?term=NCT05432232&rank=1. Accessed on October 8, 2025.
4. National Comprehensive Cancer Network^® (NCCN) Practice Guidelines in Oncology^™. ^©2025 National Comprehensive Cancer Network, Inc. For additional information, visit the NCCN website: http://www.nccn.org. Accessed on October 8, 2025.
   • Hepatocellular Carcinoma. V1.2025. Revised March 20, 2025.
   • Kidney Cancer. V1.2026. Revised July 24, 2025.
5. Solbiati, L. Humanitas Hospital. The HistoSonics System for Treatment of Primary and Metastatic Liver Tumors Using Histotripsy (#HOPE4LIVER). NCT04573881. Last updated on June 27, 2025. Available at: https://clinicaltrials.gov/ct2/show/study/NCT04573881?term=%23HOPE4LIVER&draw=1&rank=1. Accessed on October 8, 2025.
6. U.S. Food and Drug Administration (FDA). 510(k) Premarket Notification Database. Histosonics Edison System Summary of Safety and Effectiveness. Rockville, MD: FDA. Accessed on October 8, 2025.
   • No. K233466. March 13, 2024. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?ID=K233466.
   • No. K241902. October 1, 2024. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf24/K241902.pdf.  
7. Ziemlewicz T, Cho C. The HistoSonics System for Treatment of Primary and Metastatic Liver Tumors Using Histotripsy (#HOPE4LIVER US). NCT04572633. Last updated on June 11, 2025. Available at: https://clinicaltrials.gov/ct2/show/study/NCT04572633?term=%23HOPE4LIVER&draw=1&rank=2. Accessed on October 8, 2025.

Acoustic cavitation
Edison^® System
HistoSonics
Histotripsy

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage.  The member’s contract benefits in effect on the date that services are rendered must be used.  Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication.  Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.
 
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© CPT Only – American Medical Association

The requirements below are specific to the Florida Medicaid Managed Care Plan and are not a part of the Medical Policy or Clinical UM guideline approved by Elevance Health's Medical Policy and Technology Assessment Committee.
 
If the Florida Medicaid Managed Care Plan intends to deny coverage on the basis that a diagnostic test, therapeutic procedure, or medical device or technology is experimental or investigational, the Managed Care Plan shall submit a request for coverage determination to the Agency in accordance with rule 59G-1.035, F.A.C and Core SMMC Contract, Attachment II, Section VI.G.4.d.
 
Below is a list of the materials the plans are required to submit when they deny coverage as experimental/investigational: 

1. Include the CPT or HCPCS code(s)  
2. Include a list of other state Medicaid agencies and private insurers who cover the service  
3. Include information about the health service from the U.S. Food and Drug Administration  
4. Include known risks of the service and health outcomes of others who have received it  
5. Include a list of covered alternative services, if any, that could be used to treat the condition  
6. Identify a specific recipient needing the service  
7. Include the recipient’s health history  
8. Include the disease information necessitating the requested service  
9. Include a rationale for the immediacy of the review  

1. Submit the rationale used to preliminarily indicate the service is experimental/investigational
   1. Include peer-reviewed journal articles in PDF format with links to the online articles  
   2. Include evidence-based clinical guidelines reviewed by the plan  
2. Submit direct contact information (name, phone number, & email address) for the Medical Director