Portal de Periódicos da CAPES

Inflammatory response and cytokine levels induced by intralesional photodynamic therapy and 630-nm laser in a case series of basal cell carcinoma

2018; Elsevier BV; Volume: 79; Issue: 3 Linguagem: Inglês

10.1016/j.jaad.2018.02.060

1097-6787

María Jesús Suárez Valladares, Sara Calleja-Antolín, José María García Ruiz de Morales, Manuel Ángel Rodríguez Prieto, Jesús Vega-Gutiérrez,

Infectious Diseases and Mycology

To the Editor: Topical photodynamic therapy (PDT) is an alternative treatment for basal cell carcinoma (BCC), but its main limitation is the poor penetration inside the tissue. We have previously reported a high initial cure rate (100%)1Rodríguez-Prieto M.A. González-Sixto B. Pérez-Bustillo A. et al.Photodynamic therapy with intralesional photosensitizer and laser beam application: an alternative treatment for nodular basal cell carcinoma.J Am Acad Dermatol. 2012; 67: 134-136Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar and a maintenance of response in 6 years of follow-up (93.75%)2Suárez-Valladares M.J. Perez-Paredes M.G. González-Sixto B. Rodríguez-Prieto M.A. Long-term follow-up of patients with basal cell carcinoma after successful treatment with intralesional photodynamic therapy.J Am Acad Dermatol. 2016; 75: e247Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar in nodular BCC treated with intralesional PDT (I-PDT). In order to understand the mechanism of action of the technique, we analyzed the changes in the intralesional inflammatory cytokines pattern in a series of 18 BCC patients treated with I-PDT. After intralesional anaesthesia with mepivacaine, a lyophilized 5-aminolevulinic acid (5-ALA) 1% (0.2 mL/cm2) was injected inside the tumor and incubated for 120 minutes. Then, the tumor was intralesionally irradiated with a 630-nm laser beam through a fiber optic probe of 400 μm (power 1 W and fluence 180 J/cm2). All patients achieved tumor resolution after 1 or 2 sessions (16 and 2 patients, respectively), histologically confirmed by a punch biopsy in the area treated. This confirmation was made at 3 months of treatment, finding only fibrosis or scarring in the biopsy sample. To study the I-PDT–induced inflammatory response, intralesional exudates were collected with a heparinized capillary tube at baseline (T0), after 5-ALA incubation (T1), and immediately after irradiation (T2). Samples were later analyzed in a single assay for inflammatory cytokines interleukin (IL) 1β, IL-6, IL-8, IL-10, IL1-2p70, and tumor necrosis factor (TNF) α by flow cytometry (FACScanto, BD Biosciences, Franklin Lakes, NJ) using the Cytometric Bead Array (CBA) Human Inflammatory Cytokine Kit (BD Biosciences) according to the manufacturer's instructions. Statistical analysis was completed by using SPPS Statistics 22.0 (IBM Corp, Arkmon, NY). Patient data, treatment conditions, and clinical and immune responses are shown in Table I. As shown in Fig 1, A, mean values of IL-6, IL-1β, and IL-8 were significantly higher after I-PDT.Table IDemographic features and characteristics of study population (n = 18) and mean interleukin levels at different timesCategoryValueSex (F:M)9:9Age, y, mean (SD)84.11 (7.33)Histologic type BCC, n (%) Nodular14 (77.8) Sclerodermiform2 (11.1) Metatypical2 (11.1)Location, n (%) Nose11 (61.1) Check2 (11.1) Lip2 (11.1) Inner edge eye1 (5.6) Temple1 (5.6) Front1 (5.6)Depth, mm, mean (SD)2.53 (0.96)Interleukin levels, pg/mL, mean (SD)∗Limits of detection of cytokines were 7.2 pg/mL for IL-1β, 2.5 pg/mL for IL-6, 3.6 pg/mL for IL-8, 3.3 pg/mL for IL-10, 1.9 pg/mL for IL-12p70, and 3.7 pg/mL for TNFα. TNF-αT00.56 (2.36)T11.27 (4.39)T20 IL-12T00T10T20 IL-10T00T10T20 IL-6T033.52 (93.05)T12008.34 (3698.1)T21466.02 (2710.7) IL-1βT08.13 (13.7)T169.78 (84.70)T286.54 (207.93) IL-8T055.4 (74.37)T1530.7 (84.70)T2937.4 (336.3)BCC, Basal cell carcinoma; IL, interleukin; SD, standard deviation; T0, baseline time point; T1, time point after incubation with photosensitizer; T2, time point after irradiation; TNF, tumor necrosis factor.∗ Limits of detection of cytokines were 7.2 pg/mL for IL-1β, 2.5 pg/mL for IL-6, 3.6 pg/mL for IL-8, 3.3 pg/mL for IL-10, 1.9 pg/mL for IL-12p70, and 3.7 pg/mL for TNFα. Open table in a new tab BCC, Basal cell carcinoma; IL, interleukin; SD, standard deviation; T0, baseline time point; T1, time point after incubation with photosensitizer; T2, time point after irradiation; TNF, tumor necrosis factor. The data indicated a consistent inflammatory response in patients with BCC treated by I-PDT. We believe that our data provides greater clarity on the role of the immune system during PDT and reveals information about the mechanism of action of the technique. Intravenous ALA plus PDT has been described to induce TNF-α, IL-10, and IL-6, with IL-6 acting as the key inflammatory cytokine involved in the antitumoral immune response.3Gollnick S.O. Liu X. Owezarezak B. Musser D.A. Henderson B.W. Altered expression of interleukin 6 and interleukin 10 as a result of photodynamic therapy in vivo.Cancer Res. 1997; 57: 3904-3909PubMed Google Scholar However, in healthy skin treated with topical ALA plus PDT, TNF-α has been described as the driving inflammatory chemotactic factor in inflammation-associated cell dynamics.3Gollnick S.O. Liu X. Owezarezak B. Musser D.A. Henderson B.W. Altered expression of interleukin 6 and interleukin 10 as a result of photodynamic therapy in vivo.Cancer Res. 1997; 57: 3904-3909PubMed Google Scholar We did not find any changes in TNF-α or IL-10 levels. However, IL-1β, IL-8, and IL-6 increased in all patients, suggesting a different inflammatory response pattern. We speculate that different inflammatory mediators might induce different leukocyte migration and differentiation patterns responsible for the longer clinical response with I-PDT,2Suárez-Valladares M.J. Perez-Paredes M.G. González-Sixto B. Rodríguez-Prieto M.A. Long-term follow-up of patients with basal cell carcinoma after successful treatment with intralesional photodynamic therapy.J Am Acad Dermatol. 2016; 75: e247Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar or the clinical response to I-PDT could be related to the increased accumulation of protoporphyrin IX in dormant cancer cells4Nakayama T. Otsuka S. Kobayashi T. et al.Dormant cancer cells accumulate high protoporphyrin IX levels and are sensitive to 5-aminolevulinic acid-based photodynamic therapy.Sci Rep. 2016; 6: 36478Crossref PubMed Scopus (37) Google Scholar because the injected photosensitizer is able to reach the deepest skin layers.5Suárez-Valladares M.J. Rodriguez-Prieto M.A. Serra-Llusà R. Penetration of 630nm laser and 5-aminolevulinic acid in tissue with intralesional photodynamic therapy.Photodiagnosis Photodyn Ther. 2016; 16: 166-168Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In our study, increased levels of IL-8, IL-1β, and IL-6 were achieved at T1, even before irradiation. In summary, increased IL-1ß, IL-6, and IL-8 levels were achieved after I-PDT. Future research should aim to identify the subsequent immune response stimulated and specific activated cells involved in this process.