Recurrent Squamous Cell Carcinoma of the Upper Eyelid Treated With Combination Therapy of ALA Photodynamic Therapy and Surgery With Secondary Healing

SCC represents approximately 20% of nonmelanoma skin tumors, second only to basal cell carcinoma in frequency of occurrence.¹ SCC frequently appears in photoexposed areas such as the head, neck, and extremities, and its incidence increases with age.² Advanced cSCC poses a significant risk in terms of morbidity, effect on quality of life, and risk of death. Surgery remains the mainstay of treatment; however, lesions of the eyelid, lip, and nose require maximum tissue preservation.^3,4

PDT is a relatively new treatment modality that involves the administration of a photosensitizing drug and its subsequent activation by specific wavelengths of light to produce reactive oxygen species that specifically destroy target cells.⁵ PDT is only recommended for SCC in situ. 

A case of recurrent cSCC of the upper eyelid that occurred 4 weeks after initial resection is reported herein. 

A previously healthy 87-year-old female presented with a rapidly growing cutaneous tumor on the left upper eyelid. At the patient’s initial presentation after she first noticed the tumor, the tumor measured 0.5 cm × 0.3 cm × 0.2 cm in size. She had no history of topical injury and no significant past medical history. Tumor biopsy suggested a well-differentiated SCC. The lesion progressed rapidly and ulcerated in the center within 4 months. The patient reported pain and epiphora without any vision loss.

Physical examination revealed a well-demarcated cutaneous tumor measuring 5.2 cm × 3 cm × 2 cm in the left upper eyelid (Figure 1). No enlargement of the superficial lymph nodes was observed. The remaining physical examinations and preoperative laboratory tests were unremarkable. Cranial MRI showed a tumor measuring 3.6 cm × 1.5 cm and equal T1 and short T2 signal. The tumor showed hypointensity on diffusion-weighted imaging and isointensity on fluid-attenuated inversion recovery imaging (Figure 2).

Palliative surgery was performed initially. The mass and an additional 5-mm margin were resected completely under general anesthesia, followed by skin grafting from the left supraclavicular fossa for reconstruction. The pathologic findings revealed a medium-differentiated SCC. Immunohistochemical staining showed the SCC to be CK5/6 positive, 34βE12 positive, collagen type IV negative, Ki-67 positive (85%), CK7 weak positive, and p53 negative (Figure 3).

Originally, it was planned to start radiotherapy upon survival of the skin graft (Figure 4A). However, the patient did not accept the treatment choice owing to the risk of blindness associated with it. The tumor reappeared within 4 weeks of the first surgery (Figure 4B). The tumor had expanded rapidly to different areas from its first appearance (Figure 4C). The second operation involved resection with an additional 1 cm at 3 margins of the tumor, except for the bottom edge of the double eyelid line (Figure 4D).

PDT, with ALA as the photosensitizing agent, was immediately administered to the open wound.⁶ The patient was treated with PDT 3 times within 2 weeks (Figure 5). The wound healed well within 6 weeks. During the following 4 years, the patient showed satisfactory progress in both aesthetics and function, with no signs of recurrence or metastasis (Figure 6).

The treatments for SCC include surgery, radiation therapy, cryotherapy, laser therapy, electrochemotherapy, PDT, drug therapy, and gene therapy.^7-9 Treatment is individualized according to the patient’s age and health condition, as well as tumor location, infiltration, and appearance. Surgery is the preferred mode of treatment. It is performed through direct suturing, flap transfer, and free skin graft. The recommended incision range for frozen pathogenic examination is 1 cm to 2 cm beyond the edge and depth of the deep fascia.³ However, combined or general treatment is more commonly used at special sites, such as the eyelids, nose, orbits, and lips, because of incision range limitations.¹⁰ Radiation treatment is performed after surgery for head and face tumors in situ because it is well tolerated and has few complications. The radiotherapy dose must be accurate in order to minimize tissue destruction and maintain intact function and appearance. Over the past 20 years, PDT has been used in the management of malignant skin tumors. This therapy is characterized by high selectivity, decreased chance of injury, low toxicity, and repeatability, especially in terms of completeness of organ function and appearance.¹¹ 

In the case discussed in the current report, the patient was an older woman with a rapidly growing tumor close to the upper eyelid. Complete extended excision was difficult. An excision extending 5 mm beyond the edge of the tumor and viable grafting were performed during the first excision. It was planned to administer radiation therapy to the lesion region; however, the patient refused the treatment owing to the risk of blindness. The tumor reappeared within 1 month. The treatment plan was immediately modified to consist of surgery without suturing, followed by PDT. The proposed treatment plan had the following advantages: first, the incision range could be properly extended with no need for sutures. Second, the absorption of photosensitizers by residual tumor cells can be improved upon full exposure to open wounds. Third, it compensated for the depth limitations of routine PDT treatments. Fourth, PDT promotes wound healing by inducing fibroblast regeneration. Fifth, PDT inhibits bacterial growth in the surgical area. 

However, it is important to pay close attention to the following points when using PDT. First, bleeding must be completely stopped to prevent a decrease in concentration of the photosensitizers. Second, aseptic techniques must be used when performing PDT. Third, postoperative infection can be prevented in part by administration of topical antibacterial agents. Fourth, further plastic surgery may be required because of complications in specific regions, such as ectropion, chilectropion, and nasal deviation. In the current case, the patient refused to undergo further biopsy or MRI after healing. Over 4 years of follow-up, the tumor did not recur, and ectropion did not occur. 

Although the current case report discusses an effective plan for managing recurrent cSCC in a limited area, it has limitations. The most important limitation is that the margin and base were not evaluated at the pathological level to confirm whether any tumor cells existed after 3 administrations of ALA with PDT. Photodynamic diagnosis may be carried out using a topical photosensitizer instead of pathologic examination, which causes tumor cells to fluoresce under blue light. It provides a more accurate location for residual tumor cells and then reduces subsequent recurrence. More times ALA PDT should be undertaken in fluoresced areas to eliminate residual tumor cells instead of observation in follow-up. 

The treatment described herein effectively resolved a case of refractory SCC in situ using a combination of PDT and surgery, as well as secondary healing. Such treatment preserved the function of the head and face, which is important in clinical wound healing. In the future, additional combinations of surgery, PDT, and other modalities can be performed to manage recurrent SCC of the upper eyelid. 

Authors: Yuanli Guo, MD¹; Chenwei Sun, MD¹; Qiulin Gao, MD¹; Juan Wang, MD²; Xiaohui Ma, MD¹; and Hong Chen, MD¹

Affiliations: ¹Department of Dermatology, Tianjin Union Medical Center, Tianjin, China; ²Department of Dermatology, Hangzhou Third People’s Hospital, Zhejiang, China

Acknowledgments: The authors would like to thank Editage for English-language editing. 

Author Contributions: Y.G. and C.S. contributed equally to this work.

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Chenwei Sun, MD; No.190, Jieyuan Road, Hongqiao District, Tianjin, China; peterdoctor1970@sina.com

Manuscript Accepted: May 6, 2024