An Update on Recent Advances of Photodynamic Therapy for Primary Cutaneous Lymphomas

Abstract

Primary cutaneous lymphomas are rare non-Hodgkin lymphomas consisting of heterogeneous disease entities. Photodynamic therapy (PDT) utilizing photosensitizers irradiated with a specific wavelength of light in the presence of oxygen exerts promising anti-tumor effects on non-melanoma skin cancer, yet its application in primary cutaneous lymphomas remains less recognized. Despite many in vitro data showing PDT could effectively kill lymphoma cells, clinical evidence of PDT against primary cutaneous lymphomas is limited. Recently, a phase 3 "FLASH" randomized clinical trial demonstrated the efficacy of topical hypericin PDT for early-stage cutaneous T-cell lymphoma. An update on recent advances of photodynamic therapy in primary cutaneous lymphomas is provided.

Keywords: CBCL; CTCL; mycosis fungoides; photodynamic therapy; primary cutaneous lymphoma.

Figure 1

International guidelines on primary cutaneous lymphomas according to the year of publication contributed by various societies. The merged rows represent joint consensus across different societies. The color gradient shows some overlap between different guidelines.

Figure 2

The mechanism of photodynamic therapy for primary cutaneous lymphomas. The uptake of different photosensitizers (PS) into organelles depends on the cell type and photosensitizers used. Silicon phthalocyanine (Pc 4), methyl aminolevulinic acid (MAL), 5-aminolevulinic acid (5-ALA), and hypericin are the photosensitizers used in experimental lymphoma cell studies or clinical studies. After light absorption, the photosensitizer (PS) is excited to a singlet state (¹PS) and undergoes intersystem crossing to the excited triplet state (³PS). The excited triplet PS transfers its electrons to the neighbor biomolecules or oxygen to generate reactive oxygen species (ROSs), superoxide anion radical (O2•−), and hydroxyl radical (OH•) (Type I reaction) and/or by a Type II reaction through direct energy transfer to generate singlet oxygen (¹O2) to return to the ground state PS. Figure created with BioRender.com.

Figure 3

Photodynamic therapy as an adjunctive treatment in primary cutaneous lymphomas in 2 patients. A 63-year-old woman with stage IIA mycosis fungoides who received oral retinoid acid and UVB phototherapy except for the face due to the fear of skin darkening. (a) There are a few well-demarcated scaly erythematous patches on the forehead that responded poorly to topical treatments. (b) 5-aminolevulinic acid (ALA)-PDT consisted of 50 J/cm² visible light (MediLED PDT, Mediland, Taoyuan City, Taiwan) irradiance after occlusion of 5-aminolevulinic acid (Ameluz, Biofrontera AG, Leverkusen, Germany) for 3 h given every other week for 3 sessions, and strong fluorescence was shown under Wood’s light examination. (c) After 3 treatment sessions, the erythematous scaly patches over the forehead improved greatly, although a histological exam over the right forehead lesion revealed residual atypical lymphocytes. (d) A 56-year-old woman with mycosis fungoides and lymphomatoid papulosis developed new crops of papules over the V-chest despite being under treatments with twice-weekly PUVA phototherapy and weekly 10 mg oral methotrexate. (e) Vivid coral-red fluorescence was detected under Wood’s lamp illumination after occlusion with ALA for 3 h. (f) Significant improvement was achieved after a single treatment with 100 J/cm² visible light irradiation at 2-week follow-up.

Figure 4

Cutaneous B-cell lymphoma of a patient (arrows pointing to the skin lesion) who received high-potency corticosteroids and 8 infusions of rituximab before PDT: (A) before second illumination with 37 J/cm² red light after methyl-aminolevulinic acid 2.5 h occlusion and using a dermaroller to enhance drug penetration; (B) during follow-up showing clinical response [50].

Figure 5

Recent advances of PDT in the treatment of primary cutaneous lymphomas. Chemical structures of photosensitizers were retrieved from the National Center for Biotechnology Information. PubChem Compound Summary for CID 3663, Hypericin; CID 119185, Silicon phthalocyanine; CID 157922, Methyl aminolevulinate; CID 137, Aminolevulinic acid. Retrieved 13 April 2023. Abs. (nm): absorption peak wavelength(s) of light of the photosensitizer.