Recalcitrant Basal Cell Carcinoma after Grenz Ray Therapy: Introduction of High-Intensity Focused Ultrasound for Minimally Invasive Management

Abstract

Introduction

Grenz ray therapy popular in dermatology decades ago causes multiple and recalcitrant skin cancer in the treated field many years later. The treatment of choice is surgical excision, but limitations especially disfiguring scarring are a major challenge. We introduce 20 MHz high-intensity focused ultrasound (HIFU) as a new therapy overcoming the limitations of excisional surgery.

Case Presentation

A 66-year-old female, who in the 1980s had received several grenz ray treatments of the scalp, developed multiple basal cell carcinomas in the field. She had over 30 excisional surgeries including Mohs surgery in the past with many local complications but, nevertheless, recurrent cancers. HIFU treatments applied to eight basal cell carcinomas and two precancerous lesions resulted in complete clearing at 12-month control, but one recurrence after 15 months.

Conclusion

The HIFU treatment is convenient, with very few complications, and applicable to field eradication of skin premalignancies and malignancies. HIFU may fill out a hitherto unmet need of both preventive and curative treatment with better long-term control of patients with recalcitrant skin cancer after grenz ray given in the past. HIFU is a new potentially important therapeutic modality in skin oncology, combining curative treatment, field eradication, and prevention in one procedure through treatment of lesions in different states of progression.

Introduction

Grenz rays, also known as Bucky rays or soft X-rays, are electromagnetic radiation with a wavelength of 1–3 angstrom and a penetration depth in skin of around 0.5 mm [1]. After the introduction in 1923 by Gustav Bucky (1889–1962), grenz rays were commonly used for decades by dermatologists in private practice and in hospitals in the therapy of a range of dermatoses including scalp lesions and pruritic conditions. Indications included eczema, psoriasis, lichen simplex, lichen planus, genital pruritic conditions, seborrheic dermatitis, dyshidrosis, and tinea capitis [1, 2]. Treatments were often given as consecutive sessions with dosing of 100–500 cGy every 1 to 4 weeks for a period [1, 3]. Treatment was applied on doctor’s best choice, and being labeled soft X-ray, profiled to produce no sign of radiodermatitis. Dosing up to 500 cGy per session and a total dose under 50–100 Gy were considered safe [1, 3, 4].

Reports on harmful long-term effects of grenz rays, particularly multiple skin cancers in the treated field appeared in the 1980s, and use of lower total radiation dose became accepted routine [5–8]. In 2012, the National Cancer Institute reported the results of the Childhood Cancer Survivor Study, analyzing the incidence of basal cell carcinoma (BCC) in patients previously treated for various cancers by radiation therapy [9]. The study analyzed patients 5–29 years (median 18.2 years) after their first treatment and found a linear relationship between total radiation dose to the skin and risk of BCC. The risk of BCC after a typical full grenz ray treatment course in the dose range 30–50 Gy was 30–35 times higher than in the control group. The conclusion from the study was that a radiation dose to the skin of more than 1 Gy is associated with an increased risk of BCC [9]. Lag time between treatment and diagnosed BCC is often several years, and multiple cancers along with increasing treatment sequelae show up over time and presents as an increasing problem that becomes even more difficult to treat. Control and efficient therapy, thus, is demanding and mostly relies on excisional surgery, leaving scars and other local problems including hair loss and abnormal sensation. Photodynamic therapy is painful, and resource demanding and appears little used. Lasers are not directly applicable. There is a need for better therapy of recalcitrant skin cancer from grenz rays.

Recently, a 20 MHz high-intensity focused ultrasound (HIFU) device has been launched in European university hospitals and private clinics with special dedication as a safe and efficient method for noninvasive treatment of a range of dermatological conditions including actinic keratosis and BCC [10–12]. The system delivers focal points with thermomechanical insults that can be positioned directly in the skin and in the BCC under direct dermoscopic guidance. The treatment pain is momentarily only and usually tolerable without use of anesthetics. Multiple lesions including premalignant and malignant lesions can be treated in any anatomical site and in one session. Treatment does not lead to significant scarring, dyspigmentation, or hair loss and can be practiced in the scalp and in the face. HIFU relies on nonionizing physical ultrasound waves only, with no need of complementary pharmaceutical treatment except local anesthesia on demand in hyperalgesic skin. This case report demonstrates the first example of 20 MHz HIFU applied to de novo and recalcitrant BCCs after grenz ray therapy.

HIFU Methodology

The 20 MHz ultrasound device developed for dermatology (System ONE-M, TOOsonix A/S, Hoersholm, Denmark) is introduced primarily for ablative or non-ablative treatment of epidermal and intra dermal lesions thus adding a new dimension to existing HIFU systems of lower frequency targeting deeper structures including the subcutaneous space and internal organs. The applied 60–70°C thermal and mechanical insult dosed in the skin contrasts medical lasers in being tissue sparing since major caloric energy is not transmitted to the surrounding tissue. The duration of the ultrasound pulse and the ultrasound power is preset by the operator. The system provides a real-time videofeed in high resolution and color from a video camera integrated in the handpiece. Dosing and skin response are monitored directly. The field to be treated can be managed systematically with multiple HIFU doses applied “shoulder by shoulder” under video surveillance. The device has four standard handpiece options with focal depths ranging from 0.8 mm to 2.3 mm. For the treatment of BCC, the handpiece with focal depth of 1.3 mm is often preferred. This handpiece produces focal point tissue destruction in the outer dermis at the decided level of the skin [13]. The 1.3 mm focal depth aligns with the typical depth of a superficial BCC or a premalignant actinic keratosis. The 0.8-mm probe may suffice for the latter indication, and the 2.3-mm probe may be used for nodular BCC with thickness of 2 mm or less.

The HIFU energy is according to our experience effective for BCC when administered as passes of 0.9 J/dose energy level, each with pulse duration of 150 ms (6 W acoustic power). Standard ultrasound gel (Aquasonic 100^®, Parker Laboratories Inc., NJ, USA) is applied for acoustic coupling between handpiece and skin. Hair in and around the target area is not a limitation and does not need to be shaved.

Contrary to guidelines [14, 15], skin biopsy as used prior to surgical excision of precancerous lesions and BCCs in the previously grenz ray treated skin is not obligatory to HIFU treatment and often not desirable since pre-procedure biopsies cause scarring. Dormant cancer precursors are anyhow the real threat anywhere in the grenz ray treated field; treatment relies on competent clinical assessment; lesions shall ideally be treated in the early premalignant state.

Case Presentation

The patient is a 66-year-old female in good health. During the mid-1980s, she received repeated series of grenz ray treatment on her scalp to relieve itch associated with scalp psoriasis. With regular treatment of approximately one session per month over a 5-year period now and then supplemented with coal tar, salicylic acid, and prednisone, there was some relief of her condition. Over time, her hair thinned; the skin in the entire scalp area became pain-sensitive with scarring. Treatments with grenz rays had been given in a private clinic; treatment details such as single and accumulated dose were not available. She had suffered no radiodermatitis.

Within a very short period in 2020, some 35 years since the radiation treatment stopped, numerous BCCs and premalignant actinic keratoses (AKs) appeared in her scalp. A treatment regimen of surgical removal of BCCs verified by preoperative histology and cryotherapy of AKs by clinician’s assessment was initiated. Photodynamic therapy or topical treatments were not applicable due to pain sensitivity and sequelae from surgery. From 2020 to 2022, she received several cryo- and curettage treatments and a total of 13 surgical excisions of BCC by Mohs surgery. Her total number of excisions over time is estimated to about 30. Recalcitrant and de novo BCC in the increasingly damaged scalp, obviously, is an everlasting challenge; plastic surgeons and dermatologists were therefore searching another treatment modality of better therapeutic index.

In September 2022, she came with new histologically confirmed BCCs in the scalp. Ultrasound scanning (DermaScan C, Cortex Technology ApS, Aalborg, Denmark) showed echo-lucent tumors of thickness 0.5–1.3 mm in both the histologically analyzed sites as well as in a few additional lesions that could be identified based on clinical and dermoscopic examination. The patient after information granted her written consent to HIFU treatment made with or without pretreatment biopsy of suspected lesions.

Eligible lesions for treatment were outlined with a waterproof pen including a perilesional margin of 2 mm. Each selected lesion was mapped on a transparent foil to help the precise location on follow-up. The 20 MHz ultrasound scanning was used to confirm the depth of identified lesions at baseline and at subsequent follow-up visits. Due to the state of known pain-sensitive scalp, local anesthesia (25 mg/mL lidocaine + 5 mg/mL adrenaline, Amgros I/S, Copenhagen, Denmark) was administered to all lesions 10–15 min before treatment.

Lesions were treated with HIFU using the 1.3 mm probe; settings 150 ms/dose duration and acoustic energy 0.9 J/dose. 20–200 doses were applied to lesions depending on lesion extension. Treated lesions healed spontaneously with no complication or need of special treatment. Follow-up visits had been scheduled every 3–6 months to monitor cure rate/relapse, local tolerance, and newcomer lesions not identified before, see Table 1.

Table 1.

Review of patient treatment and follow-up

Date	Duration since start, months	Details
Sep 2022	Baseline	4 BCC treated
		2 AK treated
Dec 2022	3	Every treated field healed
		No recurrence or new lesions identified
May 2023	8	No sequelae in treated fields
		4 new BCCs treated
Jun 2023	10	Every newly treated field healed
		No recurrence or new lesions identified
Dec 2023	15	One recurrent lesion, session Sep 2022
		Re-treatment of this lesion
		No additional lesions identified

During the 15 months after the above-described initial clearing by HIFU, a total of 10 lesions that following routines would require biopsy followed by excisional surgery were treated with HIFU in sessions of about 30 min. Lesions healed in a few days with no complication or need of intervention. Full clearing was noted in 7 of 8 treated BCC lesions and both AK lesions. The single recurrent BCC of small size was observed after 15 months among the first six treated lesions; the lesion was retreated with HIFU. Examples of healed lesions 15 months after HIFU treatment are shown in Figures 1 and 2; the tumor with recurrence is shown in Figure 3.

Fig. 1.

Example of BCC located on the forehead of the patient with total clearing clinically after HIFU treatment. a Photo before HIFU treatment (left) and after 15 months (right). b Ultrasound cross-sectional image of skin structure before HIFU treatment (left) and after 15 months (right). The tumor presents as an echo-lucent mass at the dermo-epidermal interface; indicated by the red arrows. After 15 months, the skin structure is normalized without any sign of BCC.

Fig. 2.

Example of AK lesion located on the scalp of the patient with full remission after HIFU treatment. a Photo before HIFU treatment (left) and after 15 months (right). The lesion was keratotic and itchy before treatment; clinical diagnosis was actinic keratosis. After treatment, the skin became smooth and flat, with preservation of hair follicles within the treated field. b Ultrasound imaging of skin structure before HIFU treatment (left) and after 15 months (right). Before treatment the keratotic layer is highly echogenic due to the keratotic surface. After 15 months, the skin structure is normalized without signs of hyperkeratosis or underlying tumor.

Fig. 3.

BCC located in the scalp of the patient with signs of recurrence after previous surgical excision. a Photos before HIFU treatment (left) and after 15 months (right). A red and slightly raised eroded lesion with dilated vessels was observed, HIFU treated, but not healed. b Ultrasound cross-sectional image of the recurrent lesion after 15 months. The echo-lucent mass I the outer dermis indicated by the red arrows shows regrowth of the tumor. The tumor was retreated by HIFU and will be monitored in coming follow-up visits.

Discussion

Grenz ray treatment on many indications was popular in office dermatology for decennia [1, 2], and in a way, the topical corticoid forerunner before these were introduced in the late 1950s. Now, decades after grenz rays had reached the peak, patients show up with radiation-induced BCC in the treated anatomical sites [4–9]. The latency and severity of such recalcitrant BCCs of course vary from case to case depending on regimen, dose, and individual predisposition. Studies of cases followed over long time, however, demonstrate a direct linear relationship between skin cancer risk and total accumulated radiation dose, and with the added risk that the incidence of skin malignancy due to chronology and exposure to light and sun increases with age [9]. Most grenz ray treatments were provided when the popularity of grenz rays peaked 4–5 decades ago. Grenz ray treatment is today little used and felt obsolete. Nevertheless, as many grenz ray patients were young at the time of their treatment, the long-term sufferers with emerging and recalcitrant BCC remain a challenge in todays’ dermatology as well as in decades to come.

Topical treatments, such as photodynamic therapy, imiquimod, or 5-fluorouracil, all have limitations and low efficacy in practical use and require a high degree of patient compliance [14, 15]. As the products furthermore contain relatively aggressive pharmaceutical agents, long-term use is not feasible. Physical/surgical methods can be effective for removal of the BCCs, but such treatment may lead to disfiguring scarring, dyspigmentation, atrophy, and hair loss; the methods are therefore not attractive for the control of skin malignancies in grenz ray sufferers, who often need repeated removal of many accumulating BCCs over time. Finally, radiation therapy as practiced in oncology centers is merely contraindicated, as the negative effects from radiation are already the root of the problem [14, 15]. Non-attractive therapeutic options in today’s routine are not only a challenge for the patients but also for doctors and the healthcare system. 20 MHz HIFU for controlled tumor destruction is a logic new option based on known and validated technology.

HIFU is performed in a few minutes per lesion with or without local anesthesia. It spares hair follicles, and immediate posttreatment complaints and the posttreatment healing phase are met with acceptance by the patient and widely uncomplicated; no sutures to be removed [10–12]. As mentioned initially, the policy of obligatory pretreatment biopsy in itself causing sequelae is not, albeit rational, optimal in the long perspective of control of grenz ray-induced skin malignancies with cancers constantly showing up, some in native or early state manifested as actinic keratoses and others as BCC according to clinical diagnosis and dermoscopy. The doctor can detect clinical lesions relevant to treat and significantly reduce biopsies to deviant lesions such as suspected squamous cell carcinoma.

In conclusion, 20 MHz HIFU is introduced as a potentially safe and efficient method for management of the complex patient group with constantly emerging premalignant lesions and BCCs years after grenz ray therapy. HIFU has the potential to replace repeated surgical excision, thus eliminating the local sequelae of repeated surgery in the same anatomical site. HIFU have added value in this patient group since the method is convenient for field eradication of AK as well and thus relevant for early state precursors of skin malignancy from grenz ray. HIFU can therefore contribute to a more proactive, preventive, and efficient approach to late skin malignancy problems from grenz ray. HIFU, besides indications of AK, BCC, and Kaposi sarcoma, is already introduced to a range of other indications in dermatology exemplified by neurofibromas, granuloma annulare, etc.; translational insight from other fields of application in dermatology is available in the literature. The CARE Checklist was completed by the authors for this case report and attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539722).

Statement of Ethics

This study was conducted in accordance with the World Medical Association Declaration of Helsinki. The subject presented in the study signed a written informed consent regarding participation in treatment and publication of the case including figures. Ethical approval was according to Danish law not required for this study.

Conflict of Interest Statement

Prof. J. Serup is a principal clinical investigator in two international multicentric studies on HIFU treatment of BCC and cutaneous neurofibromatosis supported by the Bloomberg Foundation, USA, and TOOsonix A/S, Denmark.

Funding Sources

This case report was performed on equipment owned and made available for the study by TOOsonix A/S, Denmark.

Author Contributions

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of the manuscript. Jørgen Serup contributed to patient contact and consent, diagnosis, HIFU treatment, clinical photo, ultrasonic scanning, patient follow-up, figure review, literature review, and writing/revision of the manuscript. Torsten Bove and Tomasz Zawada contributed with technical support, figure review, literature review, and academic and non-biased writing/revision of the manuscript.

Funding Statement

This case report was performed on equipment owned and made available for the study by TOOsonix A/S, Denmark.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.