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DERMATOLOGICA SINICA 32 (2014) 90e92

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Dermatologica Sinica

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CASE REPORT

In situ photoimmunotherapy is ineffective in treating deeply invasivesquamous cell carcinoma

Tak-Wah Wong 1,2,3,*, Stephanie Tsao 4, Julia Yu-Yun Lee 1

1Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan2Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan3Research Center of Wound Regeneration and Repair, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan4Department of Biology, Marshall College, University of California San Diego, La Jolla, CA, USA

a r t i c l e i n f o

Article history:Received: Jan 5, 2013Revised: Apr 22, 2013Accepted: May 29, 2013

Keywords:imiquimodinvasionphotodynamicphotoimmunotherapysquamous cell carcinoma

Conflicts of interest: The authors declare that thefinancial conflicts of interest related to the subject mathis article.* Corresponding author. Department of Dermato

University Medical College and Hospital, Number 138Taiwan. Tel.: 886 6 2353535x5352; fax: 886 6 20043

E-mail addresses: Dr.kentwwong@gmail.com,(T.-W. Wong).

1027-8117/$ e see front matter Copyright � 2013, Tahttp://dx.doi.org/10.1016/j.dsi.2013.05.006

a b s t r a c t

In situ photoimmunotherapy (ISPI) can be a treatment option for selected cutaneous malignancies inpatients who are not surgical candidates. We herein report the case of a large, ulcerating poorlydifferentiated squamous cell carcinoma (SCC) affecting the foot of an elderly woman with chronicarsenicosis. The tumor failed radiotherapy, intralesional methotrexate, and 5-aminolevulinic acidphotodynamic therapy (PDT). Because the patient was reluctant to undergo amputation, the recurrenttumor was treated with ISPI using topical imiquimod application followed by PDT. Despite some initialimprovement in the superficial part of the tumor, tumor invasion to the underlying bone was detected.This case illustrates the lack of efficacy of ISIP in treating a high-risk invasive SCC.

Copyright � 2013, Taiwanese Dermatological Association.Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Squamous cell carcinoma (SCC) in patients with chronic arsenicosisis believed to be more invasive.1 The treatment of choice is surgicalexcision.2 However, alternative treatments may be needed for pa-tients who cannot tolerate or refuse surgery. Imiquimod is a topicalimmune modifier acting mainly by exhibiting agonistic activitytoward Toll-like receptors 7 and 8.3 Initially, it was approved totreat genital and perianal warts. In recent years, imiquimod hasbeen used as a safe and effective treatment option for a variety ofskin cancers including actinic keratosis, basal cell carcinoma, SCC insitu (Bowen’s disease), lentigo maligna, and extramammary Paget’sdisease.4 Although studies of imiquimod in treating invasive SCCare limited, some case reports showed encouraging outcomes.5e7

For example, Hengge and Schaller5 treated a 65-year-old manwith a 4 cm � 3 cm SCC on the temple area. The tumor was treatedby applying 5% imiquimod cream overnight three times a week. Atweek 16, the tumor was cured completely, which was also

y have no financial or non-tter or materials discussed in

logy, National Cheng Kung, Sheng Li Road, Tainan 704,26.

twwong@mail.ncku.edu.tw

iwanese Dermatological Associatio

confirmed by a histopathological analysis. There was no tumorrecurrence at the 16-month follow-up examination.5

Photodynamic therapy (PDT) destroys tumor cells by activatinga photosensitizer by a specific wavelength of light after selectiveaccumulation of the photosensitizer in cancer cells.8 In situ pho-toimmunotherapy (ISPI), which comprises PDT and topical imi-quimod, has shown promising results in patients with highlyaggressive cancers including metastatic melanoma9,10 and angio-sarcoma.11 A patient with cutaneous metastasizing melanomapreserved his left foot after ISPI.12 Although there is no reportconcerning ISPI in treating invasive SCC, these results encouragedus to treat our patient with ISPI as a limb-sparing approach.

Case report

An 85-year-old female with chronic arsenicosis visited our clinic in2005 with an 8-year history of chronic nonhealing ulcer over herright dorsal foot. A physical examination revealed a large ulcer(7.2 cm � 5 cm; Figure 1A), which proved to be a poorly differen-tiated SCC with minimal dermal invasion histopathologically. Sherefused surgical intervention or chemotherapy but accepted radi-ation therapy. There was approximately 90% improvement of thetumor (Figure 1B) with re-epithelization after radiotherapy with atotal dose of 4000 cGy over 4 months. However, local recurrencewith ulceration occurred 3 months later. Both the radiologist andsurgeon suggested amputation but the patient refused. She

n. Published by Elsevier Taiwan LLC. All rights reserved.

Figure 1 (A) A large squamous cell carcinoma presented as a chronic ulcer on the dorsal foot of an 85-year-old female. (B) The ulcer reduced by >90% after she received 4000 cGyover 4 months. (C) The tumor regrew despite repeated photodynamic therapies (PDTs; 660 J/cm2) and intratumoral methrotrexate (62 mg) injections. (D) The tumor improved witha shallower ulcer and flat edge within a month after 12-day imiquimod occlusion and 120 J/cm2 PDT (in situ photoimmunotherapy or ISPI). (E) The intact metatarsal bone prior toISPI. (F) The bone underneath was invaded by the tumor after ISPI. ISPI ¼ in situ photoimmunotherapy; PDT ¼ photodynamic therapy.

T.-W. Wong et al. / Dermatologica Sinica 32 (2014) 90e92 91

preferred less invasive approaches, such as local chemotherapyand/or PDT. Since then, she has received weekly or biweekly in-jections of 0.5 mL intratumoral methotrexate (Emthexate, 25 mg/mL; ASTA Medica Pty Limited, Auckland, Australasia) and PDT. The

PDT was done by occluding the ulcer with 4% 5-aminolevulinic acidfor 6 hours prior to exposing it to 120 J/cm2 at 120 mW/cm2 redlight (PDT 1200 lamp; Waldmann, Villingen-Schwenningen, Ger-many).13 The ulcer showed a partial response (Figure 1C) after she

T.-W. Wong et al. / Dermatologica Sinica 32 (2014) 90e9292

received 62 mg methotrexate and 660 J/cm2 over 4 months, but itrelapsed soon after. In an attempt to stimulate host immuneresponse against the tumor, 250mg (5%) imiquimod cream (Aldara;3M Pharmaceuticals, St. Paul, MN, USA) was evenly applied on theulcer, which was subsequently occluded with an air-permeablewater-resistant membrane (Tegaderm; 3M Pharmaceuticals) for12 hours daily over 12 days. One additional PDT (120 J/cm2) wasperformed on Day 6 during imiquimod therapy. She tolerated thetreatments well and the tumor improved clinically (Figure 1D).Regrettably, a follow-up radiographic examination showed evi-dence of tumor invasion to the underlying metatarsal bone, whichwas intact 5 months prior to ISPI (arrows, Figure 1E and F). Shefinally underwent below the knee amputation and was disease freeat a 4-year follow-up after surgery.

Discussion

It is well documented that both arsenic and human papillomavirus(HPV) are strong carcinogens in humans. A history of arsenicexposure and HPV seropositivity were associated with increasednonmelanoma skin cancer risks.14 However, the mechanisms bywhich HPV and arsenic interact remain to be established. Eventhough we did not examine HPV titer in this patient, it is of interestto investigate the role of HPV in skin cancer arising in patient withchronic arsenicosis.

Topical imiquimod without PDT has shown significant efficacyin treating superficial skin cancers.3 However, there is a risk ofincomplete eradication of the deeper penetrating portion of thetumor. This can result in the invasion of the underlying bone andcause bone fracture and bone pain.15 A similar case of SCC invadingthe bone of a digit was reported previously.16

ISPI is a new anticancer therapy, which intends to boost the hostimmune response against cancer. This is achieved by the activationof innate and cellular immune responses with imiquimod whentumor antigens have been generated by tumor cell destructionwithPDT.3 The tumor antigens are strong and specific. A systemic im-mune response specifically against a distant tumor can be elicitedby treating a tumor locally with PDT and imiquimod. The failure ofISPI in our patient might be attributed to the following reasons. (1)The tumor was naturally less responsive to ISPI. (2) The absorptionpeak (635 nm) of the photosensitizer protoporphyrin IX, the activemetabolite of 5-aminolevulinic acid, only penetrates the superficialdermis leaving the deeper part of the tumor untouched. By com-parison, the infrared absorption peak of indocyanine green used intreating melanomas can penetrate deeper tissues. The immuneresponses elicited by ISPI may depend on the dose and strength ofthe antigens generated from tumor destruction. The insufficientdestruction of the tumor might have limited the release of tumorantigens in our patient. It is well known that tumor antigens ofmalignant melanoma are highly immunogenic. Melanoma-associated vitiligo is the best studied example of the linkage be-tween tumor immunity and autoimmunity.17 The tumor antigens ofSCC released after ISPI might not be as immunogenic as in mela-noma. The patient had three small Bowen’s diseases (SCC in situ) onher trunk. The lesions were treated with cryotherapy and healedwithout recurrence prior to ISPI. Otherwise, we could observe the

systemic effects of ISPI. (3) The amount of imiquimod absorbedmight not be sufficient to initiate antitumor immunity. Nayloret al10 did not quantify the amount of imiquimod they used in ISPI.Nevertheless, they applied 20 cm2 � 20 cm2 imiquimod on theirpatient’s skin, an area that was approximately three times largerthan our patient.

In conclusion, though ISPI may have significant efficacy on thetreatment of metastatic melanoma, physicians should be aware ofthe limitations of ISPI in treating aggressive or deeply invasive SCCsin which the deeply invasive part of the tumor may be beyond thepenetration limit of ISPI despite positive treatment response in thesuperficial part of the tumor.

Acknowledgments

This work was supported by the Taiwan Science Councilgrants (grant nos. NSC992627E033001 and NSC1002627E033001)and the Taiwan Department of Health grant to establish centersof excellence for cancer research in Taiwan (grant no.DOH101TDC111003 to T.-W.W.). The authors also thank Dr MichaelW. Hughes for his critical review of this article.

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