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Research Letter |

Methyl-ALA–Induced Fluorescence in Photodynamic Diagnosis of Basal Cell Carcinoma Prior to Mohs Micrographic Surgery FREE

Pedro Redondo, MD, PhD; Miren Marquina, MD; Maider Pretel, MD; Leyre Aguado, MD; María E. Iglesias, MD
Arch Dermatol. 2008;144(1):115-117. doi:10.1001/archdermatol.2007.3.
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Published online

Topical application of methylaminolevulinic acid (methyl-ALA) cream induces selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in basal cell carcinoma (BCC). Irradiation of the porphyrin-enriched BCC with a Wood light leads to emission of a brick red fluorescence.1 This procedure may be termed photodynamic diagnosis (PDD). In the present pilot study, we evaluate the use of PDD for the detection of BCC and delimitation of tumor size, with retrospective comparison of fluorescent images and histopathologic results from Mohs micrographic surgery (MMS) excision margins.

Twenty patients were treated using MMS (Table). Tumors were first inspected under ordinary white light illumination in each patient, and all suspect areas were documented by photography. Methyl-ALA cream (Metvix; Photocure-ASA, Oslo, Norway) was applied as a layer approximately 1-mm thick, and a margin of 5 to 10 mm was included. Treated areas were covered by an occlusive dressing (Tegaderm; 3M, Leicestershire, England) for 3 hours. Afterwards, patients were examined under a Wood light. All suspect red-fluorescing areas were photographed (Clearstone UV-DA; DigiMed Systems, Madrid, Spain).

Table Graphic Jump LocationTable. Patient Characteristics and TSF Findings

All BCCs were excised by MMS within 1 week after fluorescence imaging without taking into consideration the fluorescence results. In the operating theater, the tumors were removed following the clinically defined margins. The first-step margins were evaluated according to the Breuninger2 guidelines (slow Mohs) using paraffin-embedded specimens and hematoxylin-eosin staining. The final wound measurement after MMS, including the wound expansion, was compared with the size and PDD images of the lesion present at the initial evaluation.

The PDD fluorescence corresponded exactly to histologic tumoral margins in 14 of the 20 patients (70%). In 7 of these 14, the PDD correlated well with both the clinical extension and the histopathologic borders of the tumors (Figure 1). In the other 7, the fluorescence area was bigger than clinically expected (Figure 2). Histopathologic study of fluorescent borders showed tumoral cells. The PDD area clearly exceeded that of the white light inspection for tumor delimitation. In 3 patients, the PDD was falsely positive (2 recurrences on recent scars) (Figure 1). In 3 other cases, no fluorescence was found (false negative): 1 sclerodermiform BCC and 2 BCCs with trichilemmal differentiation without apparent epidermal connection.

Place holder to copy figure label and caption
Figure 1.

Comparison of clinical and photodynamic diagnosis (PDD). A and B, In patient 12, there was an exact match between PDD and the clinical tumor of superficial basal cell carcinoma (BCC): the fluorescence area correlates well with the clinical picture; no basal fluorescence appears in this patient. C and D, In patient 19 a false-positive PDD occurred: on recurrent BCC on a recent scar, uniform fluorescence of the entire scar is visible, and the scarred area and normal skin surrounding the tumor shows basal fluorescence.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Patient 7 (A-C) and patient 5 (D-F) were each treated with Mohs micrographic surgery (MMS). A and D, Clinical pictures; B and E, photodynamic diagnostic photographs taken after 3-hour incubation with methylaminolevulinic acid; and C and F, clinical pictures showing the outlines of the first MMS excision (white lines). The “real margins” of the tumors confirmed by histopathologic analysis are also included (red areas) and were already delineated by the fluorescence seen in panels B and E.

Graphic Jump Location

Fluorescence imaging is a superficial technique that gives information about the superficial extent of tumors. It provides no information about the depth of a BCC, which can be determined only by histopathologic evaluation. The selective accumulation of PpIX in tumor tissue after 5-ALA applications depends on the permeation of the ALA through the stratum corneum3 and its diffusion through the dermis and epidermis. Because of its enhanced lipophilicity and better penetrative properties, methyl-ALA has a higher tissue specificity with a preferential enrichment of porphyrins in lesional skin than 5-ALA.4 The fluorescence ratios (porphyrin resistance) of BCC to normal skin are different with methyl-ALA (9:1) and 5-ALA (2:1).5

Photodynamic diagnosis has proven to be a highly sensitive method to detect neoplastic tissues, whereas PpIX, although sensitive, has a high false-positive rate because it accumulates in benign conditions like scars and inflammatory tissues. Generally, normal skin surrounding lesions presents a weak fluorescence, varying with each patient and location. The contrast between this basal fluorescence and the pathologic fluorescence needs to be intense and sharp enough to obtain a good demarcation in PDD. Occasionally, in patients with severe actinic damage, actinic keratoses close to BCCs will also fluoresce under PDD, which could increase the excision area unnecessarily. Future methods for fluorescence quantification should reduce the rate of false-positive lesions. The varying depths of the tumors or their low cellularity might provide an explanation for the absence of fluorescence in false-negative cases.

Our results suggest that fluorescence of BCC after methyl-ALA incubation, excited in the UV region of the spectrum, has characteristic features that differ from those seen in normal tissue, and this difference may be exploited for noninvasive diagnosis and the detection of lateral tumor margins. This technique could reduce the number of excisions in MMS, thus speeding up this procedure.

ARTICLE INFORMATION

Correspondence: Dr Redondo, Department of Dermatology, University Clinic of Navarra, 31008 Pamplona, Spain (predondo@unav.es).

Financial Disclosure: None reported.

Pottier  RHChow  YFLaPlante  JPTruscott  TGKennedy  JCBeiner  LA Non-invasive technique for obtaining fluorescence excitation and emission spectra in vitro. Photochem Photobiol 1986;44 (5) 679- 687
PubMed Link to Article
Breuninger  H Histologic control of excised tissue edges in the operative treatment of basal cell carcinoma. J Dermatol Surg Oncol 1984;10 (9) 724- 728
PubMed Link to Article
Svaasand  LOWyss  PWyss  MTTadir  YTromberg  BJBerns  MW Dosimetry model for photodynamic therapy with topically administered photosensitizers. Lasers Surg Med 1996;18 (2) 139- 149
PubMed Link to Article
Andersson-Engels  SJohansson  JSvanberg  KSvanberg  S Multi-colour fluorescence imaging in connection with photodynamic therapy of delta-aminolevulinic acid (ALA) sensitised skin malignancies. Bioimaging 1995;3134- 143
Link to Article
Fritsch  CHomey  BStahl  WLehmann  PRuzicka  TSies  H Preferential relative porphyrin enrichment in solar keratoses upon topical application of delta-aminolevulinic acid methylester. Photochem Photobiol 1998;68 (2) 218- 221
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Comparison of clinical and photodynamic diagnosis (PDD). A and B, In patient 12, there was an exact match between PDD and the clinical tumor of superficial basal cell carcinoma (BCC): the fluorescence area correlates well with the clinical picture; no basal fluorescence appears in this patient. C and D, In patient 19 a false-positive PDD occurred: on recurrent BCC on a recent scar, uniform fluorescence of the entire scar is visible, and the scarred area and normal skin surrounding the tumor shows basal fluorescence.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Patient 7 (A-C) and patient 5 (D-F) were each treated with Mohs micrographic surgery (MMS). A and D, Clinical pictures; B and E, photodynamic diagnostic photographs taken after 3-hour incubation with methylaminolevulinic acid; and C and F, clinical pictures showing the outlines of the first MMS excision (white lines). The “real margins” of the tumors confirmed by histopathologic analysis are also included (red areas) and were already delineated by the fluorescence seen in panels B and E.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Patient Characteristics and TSF Findings

References

Pottier  RHChow  YFLaPlante  JPTruscott  TGKennedy  JCBeiner  LA Non-invasive technique for obtaining fluorescence excitation and emission spectra in vitro. Photochem Photobiol 1986;44 (5) 679- 687
PubMed Link to Article
Breuninger  H Histologic control of excised tissue edges in the operative treatment of basal cell carcinoma. J Dermatol Surg Oncol 1984;10 (9) 724- 728
PubMed Link to Article
Svaasand  LOWyss  PWyss  MTTadir  YTromberg  BJBerns  MW Dosimetry model for photodynamic therapy with topically administered photosensitizers. Lasers Surg Med 1996;18 (2) 139- 149
PubMed Link to Article
Andersson-Engels  SJohansson  JSvanberg  KSvanberg  S Multi-colour fluorescence imaging in connection with photodynamic therapy of delta-aminolevulinic acid (ALA) sensitised skin malignancies. Bioimaging 1995;3134- 143
Link to Article
Fritsch  CHomey  BStahl  WLehmann  PRuzicka  TSies  H Preferential relative porphyrin enrichment in solar keratoses upon topical application of delta-aminolevulinic acid methylester. Photochem Photobiol 1998;68 (2) 218- 221
PubMed

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