Dermatology Online Journal

Continuous-wave Nd:Yag laser hyperthermia: a successful modality in treatment of basal cell carcinoma
Mohamed Hany El-Tonsy MD, Moetaz Mostafa El-Domyati, Ashraf Esmat El-Sawy, Wael Hosam El-Din, Tag El-Din Al-Sayed Anbar, and Hamza A Raouf
Dermatology Online Journal 10 (2): 3

Department of Dermatology, Faculty of Medicine, al-Minya University, Egypt. ruhet@internetegypt.com

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Abstract

It was observed that malignant tumor cells are more sensitive than normal cells to heat. Hyperthermia is known to be cytotoxic at temperatures above 41° C and selectively lethal to cancer cells. The aim of the present study was to evaluate the therapeutic efficacy of continuous wave Nd:Yag laser-induced hyperthermia in treatment of basal cell carcinoma (BCC). The study was performed between April 1995 and August 2000 on 37 patients with BCC selected from the outpatients of the dermatology clinic of al-Minya University Hospital. Patients were treated with continuous-wave Nd:Yag laser hyperthermia at 6-week intervals (laser output power was 10 W, spot size 8 mm, and irradiation time up to 1 minute). Following this treatment, 36 patients (97.3 %) were completely cured. Within a follow-up period of 3-5 years only one recurrence was encountered (2.7 %). Continuous wave Nd:Yag laser-induced hyperthermia should be considered as an alternative treatment for BCC. This simple, bloodless, outpatient procedure showed excellent efficacy and cosmetic result with minimal complication.

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Introduction

Basal cell carcinoma (BCC) is the most common cutaneous cancer of man. Although it generally has a relatively benign course, some instances of BCC are associated with aggressive behavior, rapid infiltration of deeper structures and even metastases [1]. Nonmelanoma skin cancer is an indication

for treatment by excision, curettage and desiccation, CO2 laser excision or vaporization, Nd:Yag laser coagulation, and systemic or topical photodynamic therapy (PDT) [2].

Heat therapy of cutaneous diseases has been used for decades. Localized heat is used in veterinary medicine for the treatment of benign and malignant lesions [3, 4]. In humans, a variety of superficial and deep tumors have been treated by hyperthermia with different degrees of success [5, 6].

Several energy sources have been used to produce local hyperthermia. They include electromagnetic energy [7], microwaves [8], sonic energy [9], and laser energy from Nd:Yag laser—referred to as laserthermia [10].

The treatment rationale is based on the fact that diseased tissue is more sensitive than normal tissue to the effects of elevated temperature; therefore, it is less able to recover after heat exposure [11].

No single mechanism of hyperthermia cytotoxicity has been generally accepted. One explanation is that cell death occurs as a result of heat-induced accumulation of nuclear proteins that restrict the rejoining of DNA strand breaks. Another theory is that heat produces plasma-membrane damage, which leads to cell death [12].

Patients and methods

This study was performed from April 1995 to August 2000 on 37 patients with BCCs, selected from the outpatients at the dermatology clinic of al-Minya University Hospital (Table 1).

Following an explanation of the procedure, possible complications, expected cure rate, and cosmetic result, participants signed formal photographic- and study-consent forms.

Histopathological examination was performed on all patients at the initial visit and at 3 months following apparent clinical disappearance of the lesions. Serial-sectioned skin biopsies were stained with H&E. Patients were followed by clinical examination and photography every 6 weeks. Laserthermia was administered every 6 weeks until the lesion was clinically resolved; the

number of treatment sessions was determined according to the clinical response. Following histopathologically confirmed cure, clinical examinations were done every 6 months for up to 5 years. Patients were also instructed to visit our clinic if any suspicious lesion appeared at the site of laser application.

The study protocol was designed to evaluate the minimum number of sessions needed to achieve clinical and histopathological cure using an 8-mm spot size. Up to two sessions for lesions 1 cm in diameter or less, three sessions for lesions 1-2 cm in diameter, and four sessions for lesions more than 2 cm in diameter. If any signs of recurrence (clinical or histopathological) appeared during the follow-up period, another session was indicated.

Three patients (8.1 %) were dropped from the study during the 5-year follow-up period.

Opmilas YAG M/ laser (1064 nm) manufactured by Carl Zeiss, Germany, was used and Fluke 51 thermocouple needle, manufactured in USA, was used to measure and control temperature of the target lesion. No local anesthesia was required because the patients tolerated the procedure easily; it was desired to avoid local anesthesia because it delays reaching the maximum temperature and allows for rapid drop of temperature. The device was calibrated by setting the desired spot size, power, and continous-mode operation (repeated pulse can allow for drop of temperature). Parameters standardized were as follows: average power 10-15 Watts and 8-mm spot size (by holding up the hand piece of ND-YAG laser device at a distance of 9 cm). Lesions larger than 1 cm in diameter were treated in segmental manner in clockwise direction. The temperature was monitored every few seconds to ensure that it was within the desired range. The thermocouple needle was kept away from the light spot. The desired temperature was maintained by pressing the hold button of the thermocouple needle. Temperature was maintained at 45° C for at least 1 minute by interrupted exposures of the target lesion to the laser light. To guard against postoperative secondary infection,the patients were asked to apply an antibiotic skin ointment to the treated site for 1 week.

The evaluation of ND-YAG laser hyperthermia as a therapeutic tool for treatment of BCC is based on the rate of clinical and histological disappearance of lesions and recurrence during 5-year followup.

Results

The patients ranged in age from 42 to 75 years with a mean age 57 ± 8.5. Males represented 23 cases (62 %), and females represented 14 cases (38 %). All BCC lesions included in the present study were located on the head and neck (sun exposed areas). One patient had scalp lesion, and the rest of patients had face lesions. The size of the lesions ranged from 0.5 cm to 3.5 cm. The duration of the lesions ranged from 3 to 18 months (Table 1). There were 27 cases of BCC that presented clinically as nodulo-ulcerative type, 4 cases of morphealike BCCs, 3 superficial BCCs, and 3 pigmented BCCs (Table 2).

Table 2. Clinical types of BCC treated by Nd: YAG laser hyperthermia

Clinical type	Number of cases (%)
Nodulo-ulcerative	27     (73)
Morphealike	4      (11)
Superficial	3      (8)
Pigmented	3      (8)

On histopathology, 24 cases of BCC were of the solid type, 8 cases of adenoid type, 4 cases morphealike, and 1 was an aggressive solid type with early adenoid formation (Table 3).

Table 3. Histological types of BCC treated by Nd: YAG laser hyperthermia

Histological type	Number of cases (%)
Solid	24     (65)
Adenoid	8      (22)
Morphealike	4      (11)
Aggressive solid with early adenoid formation	1      (3)

Prior to the study, 11 patients (69 %) received no previous treatment, 3 (19 %) had surgical removal, and 2 (12 %) had 1 session of cryotherapy.

Complete disappearance of lesions was achieved in 36 out of 37 patients (97 %) the remaining case was reported as a treatment failure (3 %) because of both clinical and histological recurrence (Table 1, case no. 13).

Figure 1a	Figure 1b
1a: Pigmented superficial BCC before treatment; 1b: Complete disappearance after two sessions of Nd:Yag laser hyperthermia.

Figure 2a	Figure 2b
2a: Pigmented superficial BCC before treatment; b: Complete disappearance after four sessions of Nd:Yag laser hyperthermia.

Figure 3a	Figure 3b
3a: Nodular BCC before treatment; 3b: Complete disappearance after four sessions of Nd:Yag laser hyperthermia

Figure 4a	Figure 4b
4a: Nodular BCC before treatment; 4b: Complete disappearance after 4 sessions of Nd:Yag laser hyperthermia.

Figure 5a	Figure 5b
5a: Ulcerative BCC before treatment; 5b: Complete disappearance after three sessions of Nd:Yag laser hyperthermia.

Complete disappearance of the tumors required two treatment sessions in 18 patients (49 %), three sessions in 12 patients (32 %), and four sessions in 7 patients (19 %).

Epidermal atrophy, basal layer hyperpigmentation, and dermal fibrosis with varying degrees of upper dermal lymphocytic infiltrate were consistent findings in all biopsies taken 3 months after last session in all patients.

Scattered islands of basaloid cells were considered a recurrence on histopathological evaluation 3 months after the final session.

The treatment failure case (Table 1, case 13) had final serial sectioned biopsy at the end of follow-up period, and no islands were observed.

The final serial-sectioned biopsies were done for all patients at the end of the follow-up period and showed disappearance of the upper dermal infiltrate and a significant reduction in dermal fibrosis; epidermal atrophy was still present, however it was not associated with significant negative cosmetic effect (Figs. 6a and 6b).

Figure 6a	Figure 6b
6a: Adenoid-type BCC showing multiple adenoid formations of basaloid cells (H&E, x25); 6b: Post-laser-hyperthermia skin biopsy showing atrophic epidermis and sparse lymphocytic infiltrate (H&E, x25).

It was evident both clinically and histologically that all patients treated for BCC by laser-assisted hyperthermia showed no effect on either sebaceous glands or hair follicles.

Treatment complications encountered were classified as follows:
Immediate (encountered during the procedure or shortly after)
1. Burning sensation, felt by all patients, was well tolerated by all patients and did not lead to stopping the session, as planned. In our personal experience, burning sensation is comparable to the pain of cryotherapy.
2. Infection developed in four patients (11 %) who needed systemic antibiotic.
Temporary (lasting less than 3 months)
3. Hypopigmentation developed in four patients (11 %) and slowly repigmented within 3 months.
4. Hyperpigmentation was encountered in one patient (3 %).
5. Alopecia at the site of laser application occurred in one female (3 %) with spontaneous hair regrowth after 3 month.
6. Clinical recurrence occured in one patient (3 %) after 1 year of the last session. The patient received another session after which neither clinical nor histopathological recurrence occurred through the rest of the follow-up period.
Permanent
7/ Permanent depressed scar was observed in 4 patients (11 %).

Changes, such as superficial erosions and crust, occurred within the 6-week interval between sessions and varied according to patient's reaction to laser hyperthermia. These changes were considered normal events after the procedure.

Discussion

Treatment of BCC depends on tumor size, location, and clinical type. Treatment modalities include excision, chemotherapy, Mohs microsurgery, curettage and electrodessication, cryotherapy, radiotherapy, retinoids, intralesional interferon, and topical treatment with 5-fluorouracil or imiquimod [12].

Some of these treatment modalities are simple and require minimal training such as radiation, curettage and electrodessication, 5-fluorouracil, and intralesional interferon. However, they all have drawbacks that range from relatively low cure rates, delayed wound healing (4-6 weeks), scarring, and hypo- or hyperpigmentation [13].

Apart from the high cure rate of Mohs micrographic surgery (MMS), the procedure needs highly qualified centers and expert histopathologists. Sometimes the procedure becomes very tedious for both patient and surgeon [13].

Our study aimed to find a new, easy treatment for BCC that leads to complete disappearance of lesions that continue for a satisfactory follow-up period (5 years) in a large percentage of cases with minimal complications.

Treatment by continuous-wave Nd:YAG laser hyperthermia in 37 patients with BCC who were followed clinically and histopathologically for 5 years revealed complete disappearance of the lesion in 36 patients (97 %) and a recurrence in one patient (3 %).Treatment by radiation and by topical 5-fluorouracil achieved 9-percent and 80-percent cure rates, respectively [13, 14].

Intralesional interferon was used to treat BCC successfully with a cure rate of 96 percent [13]. Curettage and electrodessication reported 5-year cure rate of 90 % [15]. Both simple surgical excision and cryosurgery reported 98 % cure [16, 17]. In Mohs micrographic surgery, the entire peripheral and deep margins of the submitted tissue are examined, thus explaining the high cure rate of 99.8 percent even in recurrent aggressive tumors [13]. Our study achieved a 97 percent cure rate.

The well-defined BCC less than 2 cm in size and 3-5 mm in depth is ideal for cryosurgery. Tumors in darker-skinned patients are best treated by other techniques because hypopigmentation can be expected [18]. In our study, all patients were dark-skinned (the most common skin type in Egypt), and most of the lesions were large in size. It was advisable to explore an alternative modality to treat large-sized BCCs in dark-skinned patients without causing the expected hypopigmentation.

Advantages of continuous-wave Nd:YAG laser hyperthermia in treatment of BCC were that there was no need for local anesthesia; tolerable burning sensation and pain that did not lead to stopping the session and were comparable to that of cryotherapy. However, permanent pigmentary changes were absent. Considering the cure rate, convenience, and cosmetic results of our technique compared to cryotherapy in treatment of BCC, the two modalities are comparable. However, the cost of laser-assisted hyperthermia is considerably higher.

Laser-assisted hyperthermia compared favorably to curettage followed by electrodessication, Mohs micrographic surgery, laser coagulation, and laser vaporization. Laser-assisted hyperthermia has the advantage of not leading to edema and erythema and is not associated with excessive tissue damage.

In our technique, it was evident both clinically and histologically that all patients treated from BCC by laser-assisted hyperthermia showed no effect on both sebaceous glands and hair follicles. It is recommended to carry out a separate detailed study on the actual measurement of such structures before and after treatment. The fact that malignancies are susceptible to hyperthermic treatment has been known since the early nineteenth century; however, it was not until the late 1960s that technology became available to generate high temperatures easily [12].

The aim of the hyperthermia technique is to raise the temperature of living skin containing the diseased tissue from its normal level to about 45° C. This is easily done by Nd:Yag laser beam, where a thermal penetration depth of 4-7 mm is reached [11].

The selectively lethal effect of supranormal temperatures on human neoplastic cells was demonstrated in a study performed on cancer cells in vitro compared with normal human cells. Cells were exposed to temperatures of 42-43° C for about 4-8 hours. It showed that human melanoma cells were more sensitive to heat than normal human melanocytes [19].

A number of physical factors may influence the effectiveness of hyperthermia in treating cutaneous malignancies. These factors include temperature, hypoxia, pH, tissue nutrition, vascular supply, and thermotolerance. In order for malignant tissues to be effectively destroyed, temperatures of at least 42° C must be attained. Although temperatures of 40° C can cause tissue destruction, malignant tissue regeneration occurs rapidly after such treatment [20]. High temperatures of 50° C have also been employed, but such temperatures probably cause complete tumor vascular thrombosis in addition to tissue destruction [21]. Complete vascular thrombosis does not allow for the removal of necrotic tissue and therefore inhibits rapid healing [12]. A temperature of 45° C in our study achieved considerable tissue destruction without tumor vascular thrombosis and its subsequent slow healing.

In an in vitro study done on cultured murine embryonal carcinoma cells subjected to Nd:Yag laser hyperthermia, 10 percent of cells survived a 1-minute treatment while all cells were killed after 2 minutes irradiation with 15 w [22]. These reports could explain our results in treatment of BCC with Nd:Yag laser hyperthermia that was complete cure in 97 percent. Recurrence in 3 percent of cases could be related to larger size of the lesion, aggressiveness of the histopathological type of BCC that may be recalcitrance to treatment.

Bowen disease is a form of squamous cell carcinoma in situ, in which local hyperthermia produced by disposable chemical pocket warmer was reported to be effective in treatment of 6 out of 8 cases [23].

In conclusion, Nd:Yag laser hyperthermia may be considered an efficient, easy, bloodless alternative procedure to treat BCC. Nd:Yag hyperthermia is especially useful when BCC is located in areas that are harder to treat by other modalities like the nose and areas around the eye. It showed excellent cure rate (97 %) and cosmetic results with minimal complications. There was no need for local anesthesia, and there is no contraindication for such modality.

The study protocol was approved by the faculty of medicine board, Al-Minya University, March 1995.

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