Clearance of a Thick Invasive Squamous Cell Carcinoma After Multiple Treatments with Topical Photodynamic Therapy

Introduction

S quamous cell carcinoma (SCC) is the common cutaneous malignancy on the head and neck, cosmetically sensitive areas. Currently, surgical excision is recommended as a standard treatment. However, excision of large or multiple SCC lesions, or both, potentially leads to cosmetic disfigurement. In recent years, noninvasive topical photodynamic therapy (PDT) was approved in Europe and was subsequently reported in China as a treatment for basal cell carcinoma (BCC), ^1,2 actinic keratosis (AK), ³ and Bowen disease (BD). ⁴ Both AK and BD are intraepithelial SCCs that may give rise to invasive SCC. ⁵ Topical PDT trials have been carried out in treating cutaneous SCCs; however, the recurrence rates range from 0 to 69%, suggesting that tumor-response depth is a key limiting factor for invasive SCCs, although further studies are required. ^{6 –8} A tumor-response depth of < 2–3 mm is presently recommended for nonmelanoma skin cancers. ⁹ Here, we report an unusual inoperable case of 5.5-mm-thick invasive SCC arising from AK that was successfully treated with topical PDT.

Case Report

A 53-year-old woman was seen with a 10-year history of slowly growing lesions on scalp and forehead. No history existed of previous trauma, irradiation, chronic irritation, or inherited disease. Multiple vague erythematous or keratotic lesions with crusts, ranging from 2 to 10 mm in size, were found on a right scalp or forehead, which gradually extended. Some of them formed elevated plaques. AK (bowenoid type) was confirmed by histologic examination from the plaque. These AK plaques received successive cryotherapy, laser curettage, and topical 5-FU, and disappeared quickly; however, they recurred 3 months later. She refused a local surgical excision because a large skin graft would have been involved, and she accepted a noninvasive PDT approach. Before the initial treatment, one well-demarcated 2 × 3-cm nodule with black crusts was observed on the right-front scalp. The height of the nodule above the level of the skin was ∼3 mm. Several ill-demarcated erythemas or plaques were individually scattered around the nodule (Fig. 1a). Histologic examination of a specimen taken from the thickest part of the nodule confirmed an invasive SCC with a tumor thickness of 5.5 mm, which was calculated on pathologic images taken with a photomicroscope (Nikon 90i, Tokyo, Japan) (Fig. 1b). The neighboring plaques were histologically diagnosed as AK (bowenoid type).

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FIG. 1.

Before PDT, this case clinically showed a 2 × 3-cm nodule with black crusts on the right-front scalp (a), and histologically, an atypical squamous cell mass of 5.5-mm thick (H&E, × 5) (b). 12 months after PDT, the lesion disappeared (c). Histologic biopsy taken from the previous nodule area demonstrated that the tumor cells disappeared, with reconstituted epidermis, flat rete ridges, moderate fibrosis in the dermis (H&E, × 20) (d). (Color image can be found at www.liebertonline.com/pho).

A routine workup before PDT, including physical examination, blood count, chest radiograph, and a computed tomography (CT) scan of the head, chest, abdomen, and pelvis, was performed to exclude metastasis. No significant findings were noted (for example, maxillary keratocytes and musculoskeletal malformation that are distinct manifestations of Gorlin-Glotz syndrome, numerous BCC syndromes). ¹⁰ Lung, liver, spleen, pancreas, adrenal gland, and kidney were normal. The crusts were removed by a curette for facilitating the access of the photosensitizer before application of 5-aminolevulinic acid (ALA). Topical 20% (wt/wt) ALA (Biosynth, Staad, Switzerland) in oil-in-water emulsion (Tanabe, Tokyo, Japan) was applied to the lesions with a 10-mm margin of disease-free skin, followed by sealing with thin plastic wrap and coverage with nonadhesive light-shielding dressings for ∼6 h, as described previously. ^9,11 After removal of excess cream with saline buffer, the lesions with at least a 10-mm normal margin were irradiated with a red light (wavelength, 633 nm) from a light-emitting diodes (LED) lamp (Omnilux; Altrincham, Cheshire, UK) at a light intensity of 126 mW/cm². Lesions were irradiated for 15 min at a dose of 113 J/cm². To avoid hyperthermic effects, including burning pain, the single treatment was divided into two successive sessions of 7.5 min at an interval of 30 min. The light source was calibrated before illumination by using a MACAM SR-9910 spectroradiometer (Macam Photometrics, UK). This procedure was repeated 7 times, 1 week apart, at a total cumulative dose of 791 J/cm². Moderate to serious erythemas and edemas developed on the whole treated areas during illumination. Erosion and crusting occurred after 24 h, and then disappeared within 14 days. The pain score was 7.5, with the visual analogue scale (VAS; 0, no pain; 10, worst pain) scoring. ¹² The pain was not obviously reduced by a local anesthetic administration of 10 mg/ml lidocaine, but was with cold-air analgesia. At 12 months later, complete remission was confirmed by histology biopsy taken from the previously treated area (Fig. 1d). Physical examination and CT scan showed no local or systemic metastases. No serious adverse event occurred. Cosmetic outcome was excellent (Fig. 1c). No local or systemic photosensitivity reaction was reported for ≤3 months.

Discussion

The treatment goal of SCC is complete tumor removal and minimization of cosmetic and functional defects, achieved mainly by excision surgery. For instance, micrographic (Mohs) surgery was reported to result in a 97.4% cure rate for primary SCC after 5 years of follow-up. ¹³ However, a variety of other less-invasive, effective, and cosmetically more-satisfactory treatments are available to treat cutaneous SCC. These include carbon dioxide (CO₂) laser, cryotherapy, topical chemotherapy, treatment with biologic response modifiers such as interferon, and topical PDT. Five of 13 primary SCCs achieved a complete remission with the pulsed CO₂ lasers from one study. ¹⁴ Litwin et al. ¹⁵ achieved an 86% cure rate for SCC using the topical chemotherapeutic agent fluorouracil. Kuflik et al. ¹⁶ reported a 5-year cure rate of 96% for SCC achieved by cryosurgery. Ikic et al. ¹⁷ demonstrated that the interferon treatment can produce a persistent cure (5 years) in patients with SCC (recurrence rate, 4%). A complete response rate of 63% was achieved with topical PDT in superficial SCC on face, scalp, or neck. ⁹ In contrast, the cure rate for PDT seems to be low among these therapies. However, PDT is much more available for cosmetically sensitive areas or ill-demarcated lesions.

In this report, a case of head AK progressing into SCC was shown. Both disorders responded well to topical ALA-PDT and exhibited excellent cosmetic outcomes. Currently, in view of SCC metastatic potential, topical PDT is not recommended as a first option for invasive SCC. ⁷ In a few comparative randomized controlled studies, the complete response rate varies from 54% to 74% for Bowen disease and initial SCC treated with PDT. ^4,9,18 Most nonresponsive cases are histologically seen as invasive or nodular SCCs, indicating that tumor depth is a significant predictor of treatment response. ⁹

In this case, although the tumor depth of 5.5 mm is definitely beyond the recommended response depth of 2–3 mm, ^4,19 the obvious effectiveness was observed, as shown in Fig. 1.

Three factors might be mainly involved in the complete remission of this thick tumor treated with topical PDT. One factor is penetration depth of the 633-nm light source. The biophysical calculations indicated that an LED source with a peak emission of 633 nm may have a deeper PDT action in tissue than a filtered halogen lamp of 560- to 740-nm emission, suggesting that the LED may be more effective in treating the deeper parts of tumors (>1.5 mm). ²⁰ Another factor is the penetration depth of photosensitizer ALA. Ahamadi et al. ¹¹ showed that ALA applied for 4 h penetrated to a depth of ≥ 2 mm from the lesion surface in an in vitro study of human skin biopsies. However, the two factors seem not to explain completely why the response depth reached to 5.5 mm in this case.

Another major contributing factor is possibly the outgrowing pattern of SCC. After the initial PDT treatment on the lesion, the part 3-mm thick above the level of the skin was quickly eliminated, and the whole nodule also began to shrink. Then dermal atrophy that was caused by fibrosis due to photodynamic reactions resulted in a “moving up” of the tumor mass. ⁹ Thus, these cofactors allowed the response depth to eventually reach to 5.5 mm in the subsequent multiple treatments. Other treatment parameters, such as high concentration of ALA, long duration of topical application of photosensitizing agents, and multiple treatments with a high accumulative irradiation dose may have also affected the therapeutic response. The primary complete response rates of 86% and 54% for superficial BCC and SCC, respectively, were achieved by PDT with 20% ALA. ⁹ One pharmacokinetic study showed that the highest concentration of aluminum phthalocyanine chloride (AlClPc, one photosensitive agent) was detected in normal tissue 6 h after topical application, with an average penetration depth of 1.49 mm. ²¹ Complete remission in one 7-mm-thick extramammary Paget disease (EMPD) was achieved with 10 PDT treatments, and the eventual accumulative dose was 500 J/cm. ²² Thus, multiple PDT also was necessary to obtain a sufficient effect in this case. Altogether, the therapeutic outcome is more likely decided by individual tumor features of SCC.

Based on the risk-based categories of SCC, this case can be defined as a low-risk invasive SCC because it arose from AK. ²³ Thus, this patient was expected to have a favorable prognosis before PDT. A long history of AK and SCC lesions in this case also indicated the nonaggressive disease course. Therefore, topical PDT may be recommended as the first option in outgrowing SCC without metastatic potential.

Nevertheless, this SCC subtype is rare. For the most-invasive SCC types, intralesional administration of ALA may be applied in managing some deep tumors, including this case. Henta et al. ²² reported that a vulval EMPD case with a tumor depth of 7 mm was successfully treated with the combination PDT with topical application and intralesional injection of ALA, which has been used in dysplastic Barrett esophagus, ²⁴ cervical intraepithelial neoplasia, ²⁵ carcinoma in situ of the urinary bladder, ²⁶ and Bowen disease. ²⁷ Other therapies, such as PDT after carbon dioxide (CO₂) laser, might be applied to invasive SCCs. Toshimitsu et al. ²⁸ demonstrated that the combination therapy of PDT and CO₂ laser was effective in EMPD lesions, leading to long-term complete tumor remission. Thus, for this SCC case, the area above the level of the skin might also first be ablated by CO₂ laser, and then the dermal part could be removed with subsequent combined ALA-PDT. Although this treatment may reach deep tissue, the deep ablating power of the CO₂ laser potentially causes scarring. In addition, it was not available for AK because of the ill-defined margins clinically in this case. Therefore, we did not perform the combination therapy.

Topical PDT is a feasible alternative treatment as either a single therapy or a tumor-debulking method before surgery and a strengthened therapy after CO₂ laser ablation.

Adverse effects noted in this cases were only stinging and burning sensations. They might be effectively alleviated by decreasing hyperthermic effects. Thus, the total dose of a single treatment was delivered in two sessions at an interval of 30 min for this patient. Pain perception could also be reduced by concurrent cold-air analgesia that improves the tolerability, rather than by local anesthesia, ²⁹ as shown in this case. To some extent, pain reflects nerve stimulation or tissue damage or both by reactive oxygen species(ROS), possibly aggravated by hyperthermia during irradiation. ⁶ The high pain score of 7.5 shown in this case might be related to severe destruction of local tumor tissue. The pain score is obviously higher than the score of 6.4 corresponding to the AK irradiated by LED, ³⁰ which supports the good response to PDT for our case.

Conclusion

PDT may offer a noninvasive, well-tolerated, and effective therapy for inoperable low-risk SCC with an outgrowing pattern. We suggest that tumor depth is not an absolute predictor, but only a provided reference. A personal therapeutic plan is definitely crucial for physicians performing PDT. We emphasize that it is not recommended as the first option for most patients, but may benefit patients who have poor surgical conditions or high requirements for cosmesis and quality of life.

Author Contributions

All authors had full access to all of the data in this case and take responsibility for the integrity of the data.