10.59987/ads/2014.2.77-80
Aims. About 60% of the oral cancer arise on a pre-existent potentially malignant disorder of oral mucosa like the oral proliferative verrucous leukoplakia. The treatment with the photodynamic therapy of these lesions represents, in the last years, an innovative, non-invasive and effective therapeutic possibility to achieve the secondary prevention of oral cancer. In the last decade, case reports have described patients with similar treated through a photochemical reaction induced by laser light. The aim of this study is to evaluate the effectiveness of the topical 5-ALA photodynamic therapy in the treatment of a case of Oral proliferative verrucous leukoplakia.
Case report. A female patient of 80 years old affected by white verrucous plaques on the right buccal mucosa was recruited for our case report. The right side lesion was treated with the photodynamic therapy with topical administered 5-aminolevulinic acid using the 635 nm laser light to activate the photosensitizer.
Results. The lesion showed complete response after 4 sessions of photodynamic therapy and no recurrence was noticed after 12 months.
Conclusions. The photodynamic therapy can be considered an effective treatment in the management of oral verrucous proliferative leukoplakia, but more clinical trials, with prolonged follow-up controls, are necessary to evaluate its effectiveness in the mid and long time period.
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Annali di stomatologia
potentially malignant disorders
Oral proliferative verrucous leukoplakia treated with the photodynamic therapy: a case report
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Case Report
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A. Del Vecchio
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potentially malignant disorders
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Oral proliferative verrucous leukoplakia treated with the photodynamic therapy: a case report
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                                                                                                     Case report



    Oral proliferative verrucous leukoplakia treated with
    the photodynamic therapy: a case report




                                                                                                                   li
                                                                 na
    Umberto Romeo, DDS1,2                                   but more clinical trials, with prolonged follow-up
    Nicola Russo, DDS1                                      controls, are necessary to evaluate its effective-




                                                               io
    Gaspare Palaia, DDS, PhD1,2                             ness in the mid and long time period.
    Gianluca Tenore, DDS, PhD1,2
    Alessandro Del Vecchio, DDS, PhD1,2                     Key words: photodynamic therapy, oral leuko-
                                                            plakia, oral cancer, 5-aminolevulinic acid, poten-




                                                            az
                                                            tially malignant disorders.
    1 Department of Oral and Maxillo-facial Sciences,
      Sapienza University of Rome, Italy
    2 Master EMDOLA (European Master Degree On              Introduction




                                                         rn
      Laser Applications), Sapienza University of Rome,
      Italy                                                 Oral squamous cell carcinoma (OSCC) is the fifth
                                                            common cancer in the world with an annual world-
                                                            wide incidence exceeding 300,000 cases (1). The




                                                      te
    Corresponding author:                                   disease is an important cause of death and morbidity,
    Gaspare Palaia                                          with a 5-year survival less than 50% (2). These poor
    Department of Oral and Maxillofacial Sciences,          data are mainly due to the frequent great diagnostic
    Sapienza University of Rome
    Via Caserta, 6
                                                   In       delay that characterizes the early phases of OSCC
                                                            cases. So the prevention of OSCC is the most impor-
    00161 Rome, Italy                                       tant approach to minimize its incidence and to pro-
    Phone: +39 3394522515                                   vide a better quality of life of patients. In particular,
    E-mail: gaspare.palaia@uniroma1.it                      the secondary prevention is based on the early diag-
                                                ni
                                                            nosis and management of the so-called Potentially
                                                            Malignant Disorders (PMDs), a series of pathologies
    Summary                                                 characterized by the risk of neoplastic degeneration
                                                            (2). Among the PMDs of the oral mucosa the most
                              o

    Aims. About 60% of the oral cancer arise on a           frequent is the Oral Leukoplakia (OL) (2). Clinically,
    pre-existent potentially malignant disorder of oral     OLs can be classified in two different groups: homo-
                          izi


    mucosa like the oral proliferative verrucous            geneous and non-homogeneous lesions. Moreover,
    leukoplakia. The treatment with the photodynamic        another type of OL characterized by a multifocal lo-
    therapy of these lesions represents, in the last        calization and a very high risk of malignant transfor-
    years, an innovative, non-invasive and effective        mation (about 70%) is the oral proliferative verrucous
           Ed




    therapeutic possibility to achieve the secondary        leukoplakia (OPVL) (3,4). The OPVL is more common
    prevention of oral cancer. In the last decade, case     in middle-aged women and the female-to-male ratio
    reports have described patients with similar treat-     is 4:1 (5); is of uncertain etiology and is not strongly
    ed through a photochemical reaction induced by          associated with tobacco use or alcohol with the HPV
    laser light. The aim of this study is to evaluate the   infection that may play an important role in these le-
    effectiveness of the topical 5-ALA photodynamic         sions (5). Multiple oral sites may be involved and be-
    C




    therapy in the treatment of a case of Oral prolifer-    fore malignant transformations can pass many years
    ative verrucous leukoplakia.                            up to even some decades (4).
CI




    Case report. A female patient of 80 years old af-       In the last decades many treatments were used in the
    fected by white verrucous plaques on the right          treatment of PMDs: traditional surgery (6), electro-
    buccal mucosa was recruited for our case report.        surgery, cryosurgery, laser surgery and the adminis-
    The right side lesion was treated with the photo-       tration of drugs (e.g. carotenoids, exc.) (7). Recently
    dynamic therapy with topical administered 5-            the progresses in the knowledge suggested the pos-
    aminolevulinic acid using the 635 nm laser light        sibilities of a non invasive treatment of OL with the
©




    to activate the photosensitizer.                        laser (8). Generally the laser interaction on oral mu-
    Results. The lesion showed complete response            cosa is based on the phototermic effect, that means
    after 4 sessions of photodynamic therapy and no         to have the possibility to cut the tissue to perform a
    recurrence was noticed after 12 months.                 biopsy (9,10). Another effect of laser on soft tissue is
    Conclusions. The photodynamic therapy can be            a photochemical effect, the so called photodynamic
    considered an effective treatment in the manage-        therapy (PDT) that is based upon a photochemical
    ment of oral verrucous proliferative leukoplakia,       laser light induced reaction, strictly directed on patho-

    Annali di Stomatologia 2014; V (2): 77-80                                                                     77
    U. Romeo et al.


    logic cells, permitting a safe and complete removal of      cided to treat the lesion with a minimal invasive tech-
    the lesion without sacrifice of healthy tissue (11). The    nique: the topical 5-ALA-PDT. The consensus for the
    PDT involves three components: light, a photosensi-         treatment from the patient was required before the
    tizer and oxygen. A photosensitizer, or its metabolic       start of the therapy.
    precursor, is locally applied upon the lesion. The acti-    The formulation of 20% gel of 5-ALA used in our




                                                                                                                           li
    vation of the photosensitizer with a low level laser        study was prepared using 25% of Lutrol F127 (Basf
    light, determines the transition of the agent from a        Chemtrade GmbH, Burgbernheim, Deutschland) and




                                                                    na
    low energy ground state to an excited singlet state.        1% of Carbopol 971P (Lubrizol, Cleveland-Ohio
    The singlet state can react with endogenous oxygen          State, USA). Double concentrated gels of Lutrol F127
    to produce singlet oxygen and other reactive oxigen         and Carbopol 971P in water were separately pre-
    species (ROS), causing a rapid and selective de-            pared prior to mixing. After refrigerating at 4° C, the




                                                                  io
    struction of the target tissue (Fig. 1).                    solution of Lutrol F127 was mixed with equal volume
    These photochemical induced reactions lead in many          of the Carbopol 971P gel and the mixture was stored
    ways to the destruction of neoplastic tissues; as a         at 4° C. Prior to use, 800 mg of gel was mixed with
    first, ROS kill directly tumor cells; in other cases, PDT   200 mg of 5-ALA (Fagron GmbH, Barsbuttel,




                                                               az
    damages the tumor associated vascular tissues,              Deutschland). The formulation was used within 3
    leading to thrombus formation and subsequent tumor          hours after the preparation. A thin layer of gel was
    infarction. Moreover PDT can also elicit an immune          applied topically on the lesion using a microbrush
    response against tumor cells (12). The advantages of        (Fig. 2). For the first 10 minutes after the application




                                                            rn
    the PDT in the treatment of OL were confirmed in            of the gel, three cotton rolls were placed onto the ori-
    many studies in literature (8, 12-14). On the other         fices of majors salivary glands to avoid the dilution of
    hand, PDT in several cases, requires multiple ses-          gel by the saliva. In addition, during this period, the




                                                         te
    sions of irradiation to achieve complete regression of      doctor controlled the salivary flow by intermittent suc-
    the lesion and the costs of the laser and of the photo-     tion. The gel was left 1.5 hours over the lesion to per-
    sensitizers are high.                                       mits its gathering into target cells. During this period,
    A lot of natural and synthetic agents have photosensi-      a gauze was placed over the lesion to avoid the re-
                                                      In
    tizing potential, but the 5-aminolevulinic acid (5-ALA)
    is one of the most important photosensitizer in the
                                                                moval of gel. For the activation of the photosensitizer

    management of OL. For the treatment of pre-malig-
    nant and malignant lesions in the oral cavity has been
    used PDT with topical administered 5-ALA. Due to
                                         ni
    the limited depth of topical 5-ALA administration, and
    the limited light penetration of 635 nm laser light, the
    use of 5-ALA is restricted to superficial lesions (1-2
    mm) such as homogeneous flat leukoplakia, ery-
                            o

    troleukoplakia and verrucous leukoplakia (15). 5-ALA
    is rapidly cleared from the tissue and the body within
                        izi


    48 hours and skin photosensitivity lasts less than 24
    hours (15). The aim of this study is to report the man-
    agement of a clinical case of OVPL trough the PDT
    obtained with the locally administration of a 20% gel
           Ed




    of 5-ALA.

                                                                Figure 1. Clinical aspect of the lesion before 5-ALA-PDT
    Case report                                                 treatment.

    A female patient of 80 years was recruited for the
    C




    study; history and general physical investigation re-
    vealed no relevant findings and no tobacco-chewing
CI




    or smoking habit was reported from the patient. The
    clinical examination of the mouth revealed painless
    white verrucous plaque lesion with multiple peaks on
    the buccal mucosa bilaterally (Fig. 1). A clinical provi-
    sional diagnosis of OVPL was made considering the
    multifocal, verrucous aspect of the lesion (16) and,
©




    subsequently, this diagnosis was confirmed by inci-
    sional biopsy of the diseased mucosa. The histologi-
    cal examination revealed proliferative corrugated hy-
    perkeratosis, acanthosis, mitoses, broad rete ridges
    and inflammatory cell infiltrated on the connective tis-
    sue. The lesion was photographed for further evalua-
    tion. Considering the dimension of the lesion, we de-       Figure 2. Application of 20% 5-ALA gel on the lesion.

    78                                                                               Annali di Stomatologia 2014; V (2): 77-80
    Oral proliferative verrucous leukoplakia treated with the photodynamic therapy: a case report


    was used a diode laser of 635nm (Doctor Smile-Den-
    tal Laser, Vicenza, Italy) (Fig. 3). Each application
    consisted of five 3 mins and one 100s irradiations
    with five 3-minutes breaks for a total of 1000s (flu-
    ence rate: 100mW/cm2, total energy dose 100J/cm2)




                                                                                                                             li
    using the fractionated protocol of irradiation de-
    scribed by Chen et al. (14). With this irradiation proto-




                                                                     na
    col, the lesional epithelial cells have the possibility to
    regenerate new PpIX and obtain new oxygen during
    multiple 3-minutes resting period. The laser has been
    set at a very low power (100mW), to take advantage




                                                                   io
    only of the photochemical effect of the laser, without
    the overheating of the targeted tissues. The treatment
    was performed twice a week until the clinical resolu-
    tion of the lesion. At the end of the therapy, the pa-         Figure 5. Clinical aspect after 12 months of follow-up.




                                                                az
    tient was arranged for a follow-up schedule once a
    month and clinical photographs were taken at each
    patient’s visit to evaluate the clinical outcome of PDT.
    The lesion showed complete response after 4 treat-             Discussion




                                                             rn
    ments of PDT (Fig. 4). The treatment was painless
    and the patient did not require either local anesthesia        In our case the results are encouraging. The suc-
    during the irradiation or analgesics drugs after the           cessful clinical outcome could be due to the gel




                                                          te
    treatment. The examination at 6 months after the last          preparation, the fractionated protocol of irradiation
    session of PDT showed that the OPVL disappeared                used, and the characteristics morphological, histolog-
    completely with a good healing of the mucosa. The              ic and biological features of the lesion. The 20% 5-
    patient was satisfactory for the treatment and the fol-        ALA gel was adherent to oral mucosa and partially re-
    low-up at 12 months showed no recurrence (Fig. 5).
                                                       In          sistant to the dilution of saliva. This aspect is very im-
                                                                   portant because the gel form helped the absorption of
                                                                   5-ALA from the mucosal surface. The fractionated
                                                                   protocol of irradiation allows the regeneration of new
                                                                   PpIX by the lesional epithelial cells and the obtaining
                                                ni
                                                                   of new oxygen during multiple 3-minutes rests. So re-
                                                                   sults in a more successful clinical outcome for the
                                                                   therapy of OVPL. Moreover the verrucous appear-
                                                                   ance of this lesion provided a large area of retention
                              o

                                                                   for the gel, resulting in a difficult removal of 5-ALA
                                                                   from salivary flow.
                          izi


                                                                   One of the main limitation of the 5-ALA-PDT is the
                                                                   low depth of penetration of the topical photosensitiz-
                                                                   er. For this reason, this therapy is restricted to super-
                                                                   ficial lesions of 1-2 mm of thickness.
           Ed




                                                                   Previous study demonstrated the effectiveness of
                                                                   this therapy in the management of OL. Fan et al.
    Figure 3. Irradiation with 635 nm diode laser.                 (13) treated 12 patients with oral dysplastic lesions
                                                                   using orally administered ALA. All 12 patients
                                                                   showed regression of the lesion of the lesions to
                                                                   normal or less dysplastic. Kübler et al. (13) treated
    C




                                                                   12 patients affected by leukoplakia of the oral mu-
                                                                   cosa for several years. 20% ALA cream was applied
CI




                                                                   to the lesion for 2 hours. Five patients showed com-
                                                                   plete response, four patients showed a partial reso-
                                                                   ponse, and in three patients treatment showed no
                                                                   response. Sieron et al. (14) treated 12 patients with
                                                                   lesions that affected a variety of intraoral sites using
                                                                   10% ALA cream. Irradiation was performed in 6-8
©




                                                                   sessions of therapy. A complete response was ob-
                                                                   tained in 10 patients, with one recurrence during 6
                                                                   months. The potential advantages of the PDT for
                                                                   treating the OPVL are: moderate side-effects, possi-
                                                                   bility to give repeated doses without cumulative tox-
    Figure 4. Clinical resolution after 4 treatments of 5-ALA-     ic effects, excellent aesthetic results with healing
    PDT.                                                           process characterized by little or no scars and re-

    Annali di Stomatologia 2014; V (2): 77-80                                                                                79
    U. Romeo et al.


    duction of pain during the treatment. The poor side        References
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CI
©




    80                                                                                 Annali di Stomatologia 2014; V (2): 77-80
