Da lieu - VI

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Dermatologica Sinica

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BRIEF REPORT

Circumferential scouting punch biopsies to delineate surgical margin for dermatofibrosarcoma protuberans

Tsung-Mao Huang¹, Shyh-Jou Shieh², J. Yu-Yun Lee¹, Tak-Wah Wong^1,3,4,*

¹ Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

² Department of Plastic and Reconstructive Surgery, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

³ Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

⁴ Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan

ARTICLE INFO

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft-tissue tumor involving the dermis and subcutaneous tissue with a high local recurrence rate after standard excision. Mohs micrographic surgery offers a lower recurrence rate. However, the procedure requires multiple stages of excision with intra­operative histopathological mapping, which is time consuming and expensive. We report our experience of using circumferential scouting punch biopsy technique in five patients to determine in advance the resection margins for DFSP prior to wide excision. Multiple 4 mm punches, usually eight in number, were performed 1—2.5 cm around the palpable borders of DFSP to delineate the resection margins in five consecutive patients. Tumors were excised at a later date along the margin defined by these biopsies and the wounds were repaired with skin graft. The operation was completed in 2 hours in all cases excluding one that required frozen sections for deep margin. No recurrence was noted 2—10 years after the operations. The results suggest that circumferential scouting punch biopsies before wide excision may be an alternative method to define the resection margins for DFSP when Mohs surgery is not available.

Copyright © 2011, Taiwanese Dermatological Association.

Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous soft tissue tumor of intermediate malignancy.¹ It is characterized by progressive local growth and a propensity for local recurrence, but rarely metastasizes. Surgical excision can be chal­lenging due to the invasive nature that results in high local recur­rence rates.² Recurrence rates of DFSP range from 30% to 60% with surgical margins less than 3 cm, but reduce to a mean of 18% with resection margins greater than 3 cm.³ However, wide margins may be difficult to obtain for lesions on the head and neck due to potential tissue loss equals loss of critical structures. Mohs surgery is a technique of controlled skin cancer removal by mapping and serial frozen sections of resection margins. Each stage of tissue removal and microscopic examination is repeated until all margins are clear of cancer.^4-6 Removal of DFSP by Mohs surgery provides maximal

*     Corresponding author. Tak-Wah Wong, Department of Dermatology, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan. Tel.: +886 6 2353535x5352, 5417; fax: +886 6 2766180.

E-mail addresses:   Dr.kentwwong@gmail.com, twwong@mail.ncku.edu.tw

(T.-W. Wong).

tissue conservation with a lower recurrence rate (0—6%).^3—6 However, Mohs surgeons are not available in many medical facili­ties. Moreover, it may require several hours to complete a large resection by Mohs surgery.^7,8 Longer operation time may increase medical expense.^7,8

Without Mohs surgeons in our region, we tried a different approach by performing multiple punch biopsies around the tumor in the clinics to determine the resection margins first and then performed wide excision at a later date. We treated five consecutive DFSP patients with this approach.

Patients and methods

During a 10-year period (1999—2009), five patients with DFSP (Table 1) underwent circumferential punch biopsies in the clinic several days before wide excision. We first outlined the tumor border by palpation, and then performed multiple 4 mm punches, usually eight in number, at a distance 1—2.5 cm around the palpable border. For the tumor located near the nipple, two to three rows of punches were carried out in order to preserve more normal areolar tissue. The punch specimens were processed for routine histopathology exami­nation. The whole tumor was then excised in a few days in the

1027-8117/$ — see front matter Copyright © 2011, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.dsi.2011.09.002

T.-M. Huang et al. / Dermatologica Sinica 30 (2012) 16—20 Table l Demographic data of 5 patients with dermatofibrosarcoma protuberans.

Patient/Sex/Age	Location	Size	Numbers of punch	Resection margin to tumor: shortest distance/longest distance	Operation time	Outcome
1/F/34	Right upper chest near axilla	7.3cm x 6.2 cm	8	2 cm/2 cm	2 hours 5 minutes	No recurrence at 10 years
2/M/37	Left thigh	4.5cm x 3cm	8	2 cm/2 cm	1 hour 50 minutes	No recurrence at 9 years
3/F/30	Right breast	2.8cm x 1.5 cm	17	1 cm/2 cm	30 minutes	No recurrence at 9 years
4/F/22	Right breast	3.5cm x 4.2 cm	8	1.2 cm/2 cm	2 hours 4 minutes	No recurrence at 3 years
5/M/48	Scalp	5.5cm x 4.5 cm	8	2.5 cm/2.5 cm	4 hours 28 minutes*	No recurrence at 2 years
Mean i standard		4.7 i 1.8 cm x 3.9	10 i 4	1.7 i 0.6 cm/2.1 i 0.2 cm	2 hours 11 minutes ±1 hour	6.4 ± 3.6 years
deviation		i 1.8 cm			26 minutes
Age: 34 i 10

* Including 2 hours waiting for frozen section results during operation.

operating room along the lines drawn by connecting the tumor-free dots determined by punch biopsy. Frozen sections were completed during operation to check the deep margin when necessary.

Patient 1 was an otherwise healthy 34-year-old woman who presented with a small scar-like nodule that had been enlarging slowly for 17 years on her right upper chest near the axilla (Figure 1A). Histopathologically, the tumor showed a diffuse, extensive proliferation of spindle cells throughout the dermis with invasion to the subcutaneous tissue (Figure 1B). The findings were consistent with DFSP. In this case, we tried photodynamic diagnosis, a technique that utilizes the preferential accumulation of photosensitizer in tumor cells with a 6-hour occlusion of 2% 5-aminolevulinic acid (Merck, Darmstadt, Germany) to define the tumor margin.⁹ It was based on the fact that tumor cells tend to accumulate more protoporphyrin IX, the active metabolic product of 5-aminolevulinic acid, and emits red fluorescence under Wood’s light excitation.¹⁰ However, no visible fluorescence was detected. The negative results might be attributed to insufficient trans­epidermal delivery of photosensitizer through an intact stratum corneum¹⁰ or the deep location of the tumor. Eight circumferential

4 

mm punch biopsies were performed 2 cm beyond the palpable border of the mass (Figure 1C). Patient 2, a 37-year-old man, with a DFSP on his left thigh for 10 years was treated with same tech­nique to delineate the tumor before excision (data not shown).

Patients 3 and 4 had pathology proven DFSP on the breast (Figures 2 and 3) where maximal preservation of breast tissue was desirable. In Patient 3, the tumor margin toward the nipple was delineated by performing a total of seven punch biopsies in three
rows (1 cm, 1.5 cm and 2 cm, respectively) from the tumor (Figure 2A). Additional 10 biopsies were taken 2 cm beyond the palpable tumor margin in other directions. In Patient 4, eight punch biopsies were performed 2 cm from the palpable border of the tumor except for the areola border where the punch was done 1.2 cm from the tumor (number 6, Figure 3B). Patient 5’s DFSP was located on his scalp. There was no palpable lymphadenopathy in the neck, submental and postauricular areas. Computed tomog­raphy scan revealed no direct bony destruction from the scalp tumor. Eight punch biopsies were performed with 2.5 cm distance beyond the border of the palpable mass because tumor of this location was reported to be more invasive.¹¹

Results

All biopsy specimens were negative for tumor cells. The tumors were excised along the margin connected by these biopsies and to the depth of fascia except in Patient 5. Frozen section during operation confirmed that the lateral resection margins were free of tumor but the horizontal sections of the tumor base showed tumor invasion into the deep subcutaneous fat. The underlying periosteum was removed. Skin defects were repaired with split thickness skin graft (STSG) in all patients. The total operation times ranged from 30 minutes to 4 hours 28 minutes (mean: 2 hours 11 minutes ±1 hour 26 minutes). The longest operation time was with Patient 5 where a frozen section was required which took 2 hours. No clinical recurrence was noted in all patients during 2 years to 10 years (mean: 6.4 ± 3.6 years) of follow-up after operation.

Discussion

In this small case series, we demonstrated that peripheral resection margins of DFSP can be drawn in advance by multiple punch biopsies around the tumor before performing wide excision in the operating room. This procedure saved time and the expense of surgery, and the outcome appeared satisfactory. There is a concern that this scouting punch biopsy can only check a small fraction of
the lateral margins and does not check the deep margin. However, the purpose of using this scouting biopsy technique is to find a reasonable estimation of resection margins so that maximal tissue preservation can be achieved when Mohs surgery is not available. With this approach, the resection margins of the excised tumor can then be checked by routine histopathological study. If necessary, additional tissue may be excised in a follow-up surgery. Clearly, this scouting punch biopsy technique does not check the deep margin of DFSP, which can be determined by frozen section during surgery when necessary after the tumor has been removed by wide excision. Confirmation of free deep margin is critical in tumors that are associated with increased risk of local recurrence in specific loca­tions, such as the scalp, due to higher incidence of deep tissue involvement.¹¹ This is exemplified in the scalp tumor in Patient 5.

Appert et al reported that multiple scouting biopsies before Mohs micrographic surgery has been used in extramammary Paget’s disease to define the peripheral surgical margin.¹² In extramammary Paget’s disease, the tumor infiltration at the periphery primary involves the epidermis. This is in contrast to DFSP where the tumor infiltrates the dermis and subcutaneous tissue. The tumor cells in the infiltrating border of DFSP may be few in number and show little dysplastic changes, thus may be difficult to be differentiate from normal dermal fibroblasts in hematox- ylin—eosin sections. Even with CD34 staining, it may be difficult to differentiate infiltrating tumor cells from the normal CD34-positive interstitial dendritic cells and cells around hair follicles and sweat glands in normal dermis.

For most of our patients, eight punches were sufficient for delineation of lateral resection margin and the surgery had been shortened to approximately 2 hours. The surgery time for Patient 5 was 4.5 hours because of the extra time required for an intra­operative frozen section to evaluate the deep resection margin and the removal of the underlying periosteum.

In DFSP, initial adequate excision is critical because metastasis is invariably preceded by two or more local recurrences.³ Insidious spread of a tumor into the clinically normal appearing skin around the tumor is not uncommon.¹³ Most surgeons suggested that a margin of at least 3 cm around the tumor with tissue down to the fascia should be removed to minimize the risk of recurrence.⁴ Even with such wide excisions, recurrence rates from 11% to 20% have been reported.⁴ The closest margin in our case was 1 cm and no recurrence has been noted 2—10 years postoperatively (mean 6.4 ± 3.6 years). It is possible that the favorable outcome in our patients might be because of the tumors had less infiltrative borders. More case studies are needed before a definite conclusion can be made. A proposed approach of surgical intervention of this tumor is shown in Figure 4.

In summary, we reported five patients with DFSP successfully treated with surgical excision in which the lateral resection margin was predetermined before excision by scouting punch biopsy technique in the outpatient clinics. The patients remained tumor free from 2 years to 10 years after tumor excision. The results suggest the lateral resection margins of DFSP can be determined by this type circumferential scouting punch biopsy technique in selected tumors when maximal normal skin preservation is highly desirable and Mohs surgery is unavailable. However, studies of more cases are needed to evaluate the value of this approach.

References

1.   Gloster Jr HM. Dermatofibrosarcoma protuberans. J Am Acad Dermatol 1996;35:355-74.

2.   Arnaud EJ, Perrault M, Revol M, Servant JM, Banzet P. Surgical treatment of dermatofibrosarcoma protuberans. Plast Reconstr Surg 1997;100:884—95.

3.   Nelson RA, Arlette JP. Mohs micrographic surgery and dermatofibrosarcoma protuberans: a multidisciplinary approach in 44 patients. Ann Plast Surg 2008;60:667—72.

4.   Ratner D, Thomas CO, Johnson TM, et al. Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans. Results of a multiinstitutional series with an analysis of the extent of microscopic spread. JAm Acad Dermatol 1997;37:600—13.

5.   Gloster Jr HM, Harris KR, Roenigk RK. A comparison between Mohs micro­graphic surgery and wide surgical excision for the treatment of dermatofi­brosarcoma protuberans. J Am Acad Dermatol 1996;35:82—7.

6.   Snow SN, Gordon EM, Larson PO, Bagheri MM, Bentz ML, Sable DB. Dermato­fibrosarcoma protuberans: a report on 29 patients treated by Mohs micro­graphic surgery with long-term follow-up and review of the literature. Cancer 2004;101:28—38.

7.   Smeets NW, Krekels GA, Ostertag JU, et al. Surgical excision vs Mohs’ micro­graphic surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet 2004;364:1766-72.

8.   Essers BA, Dirksen CD, Nieman FH, et al. Cost-effectiveness of Mohs micro­graphic surgery vs surgical excision for basal cell carcinoma of the face. Arch Dermatol 2006;142:187—94.

9.   Becker-Wegerich PM, Fritsch C, Schulte KW, et al. Carbon dioxide laser treat­ment of extramammary Paget’s disease guided by photodynamic diagnosis. Br J Dermatol 1998;138:169-72.

10.  Wong TW, Sheu HM, Lee JY, Fletcher RJ. Photodynamic therapy for Bowen’s disease (squamous cell carcinoma in situ) of the digit. Dermatol Surg 2001;27:452—6.

11.  Loss L, Zeitouni NC. Management of scalp dermatofibrosarcoma protuberans. Dermatol Surg 2005;31:1428-33.

12.  Appert DL, Otley CC, Phillips PK, Roenigk RK. Role of multiple scouting biopsies before Mohs micrographic surgery for extramammary Paget’s disease. Der­matol Surg 2005;31:1417-22.

13.  Sondak VK, Cimmino VM, Lowe LM, Dubay DA, Johnson TM. Dermatofi­brosarcoma protuberans: what is the best surgical approach? Surg Oncol 1999;8:183—9.

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Dermatologica Sinica

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CORRESPONDENCE

Good therapeutic outcome of radiotherapy in large facial skin cancers

Introduction

Reports of treating large facial skin cancers by radiotherapy are scant.^1-3 Complete resolution of a huge exophytic angiosarcoma of the central face could be achieved by radiotherapy with relapse- free survival of 5 years.³ In this report, we describe two cases of large squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) treated by radiotherapy with good clinical and cosmetic results. Although these tumors might be amenable to conventional surgery or Mohs micrographic surgery followed by reconstruction surgery, the cosmetic and functional outcomes may not be satisfactory.

Case reports Case 1

An 88-year-old woman was referred from a local hospital for a 4.5 cm x 3.0 cm dehiscent wound after wide excision of a moder­ately differentiated squamous cell carcinoma 2 weeks earlier (Figure 1A). Examination revealed intense inflammation of the right cheek with multiple keratotic tumors near or contiguous to the ulcer. Considering the extent of tumor involvement, the size of dehiscent wound and old age of the patient, radiotherapy was sug­gested. A computed tomography scan for tumor staging revealed residual tumor mass up to 2.0 cm in diameter with focal skin thick­ening without invasion of deeper tissues or metastasis. The radia­tion field included the gross tumor, the neighboring area of skin thickening and a 1.5-cm free margin. Using intensity-modulated radiation therapy, a total dose of 7000 cGy (in 200 cGy daily frac­tion) by 6 MV photons was initiated. Substantial clinical improve­ment was noted after eight fractions (1600 cGy administered) (Figure 1B), and a complete healing of the ulcer with resolution of the tumors and inflammation was noted 6 weeks post­radiotherapy (Figure 1C). There was no tumor recurrence at a 15- month follow-up.

Case 2

A 42-year-old woman presented with a 10-year history of a slowly enlarging keloid-like tumor with a shiny, nodular surface and telan­giectasia (Figure 2A). The tumor was 2.5 cm x 3.0 cm x 0.4 cm in size, and occupied the entire left nasolabial area, including the

philtrum and vermilion border of the upper lip with partial obstruction of the nostril. A skin biopsy revealed nodular basal cell carcinoma extending to the dermo-subcutaneous junction. The patient opted for radiotherapy. The radiation field encom­passed a 2-cm free margin around the tumor with a customized Ceroband® block to shield the right nasal alar cartilage and lower lip. Radiation therapy with 6 MeV electrons was prescribed to an 80% depth to a total dose of 7000 cGy in 200 cGy daily fractions. After radiotherapy, the tumor resolved completely with residual scarring. There was no local recurrence at a 2.5-year follow-up (Figure 2B).

Discussion

Radiation therapy is an important treatment modality for non­melanoma skin cancers (NMSC), especially in cases where surgery, cryotherapy, electrodesiccation and topical chemotherapy are con­strained by the tumor’s size, depth or location (such as the lip, ear, nose and periorbital region) or the patient’s age, medical co-morbidity or personal preference.

Radiation therapy for cutaneous malignancy has declined in recent decades because of drawbacks (such as radiodermatitis and radiation-induced malignancy), and the advent of other thera­peutic modalities. However, the risk of radiodermatitis and radiation-induced malignancy has been much reduced with modern and fractionated radiation therapy. This treatment option is often overlooked by dermatologists nowadays, and radiotherapy is more commonly administered as an adjuvant therapy in high­risk NMSC or when tumor-free margins are inadequate.

For the treatment of BCC, surgery appears to have the lowest recurrence or failure rates, and thus is more effective than radio­therapy according to a Cochrane Review.⁴ Nevertheless, radio­therapy is a good option for elderly patients with tumors on the mid-face, including the nose, inner canthus and lower eyelid.¹ In a series of 115 previously untreated or recurrent basal cell carci­nomas treated with radiation therapy, the local control rates at

5 years were 95% for the stage I and II tumors and 56% for the stage III and IV tumors.⁵ The authors concluded that radiation therapy can achieve high cure rates for stage I and II basal cell carcinomas and is a relatively effective method for treating recurrent basal cell carcinomas, with cure rates surpassed only by Mohs micro­graphic surgery.⁵

In cases of SCC, radiotherapy can be a definitive treatment option when considering cosmetic appearance and function, but high-risk SCC should ideally be excised with the aim to obtain adequate margins.¹ In the guidelines proposed by the National Comprehensive Cancer Network for treating SCC, wide excision (10-mm margins if achievable) or Mohs micrographic surgery are recommended for high-risk tumors (>4 mm in thickness, Clark level IV to V, moderate to poor differentiation, presence of perineu­ral invasion and recurrent tumors). Radiotherapy is kept as an adju­vant treatment if clinically warranted.⁶

No randomized controlled trials (RCT) have examined the effec­tiveness of radiotherapy in comparison with other treatments for SCC,⁷ and there was only one RCT comparing surgical excision with frozen-section margin control to radiotherapy in primary facial BCC. ⁸ According to recent statistical data, the 5-year recur­rence rates of Mohs surgery and the standard excision were 1% and 5.3% respectively for BCC, and 3% and 8% respectively for SCC.⁹ In comparison, radiotherapy alone had higher 5-year recur­rence rates of 7 to about 10% for both BCC and SCC.⁷ Further clinical follow-up data from 604 cases of BCCs and 104 cases of SCCs treated by office-based radiation therapy showed 5-year cure rates of 92.7% and 94.4%, respectively, and attained 78.6% to about 84% cure rates in 15 years.¹⁰

In our first patient, the treatment posed a significant challenge because of the large dehiscent wound and the presence of multiple SCCs on the face. Radiotherapy was considered, but there was a concern for poor skin tolerance because of the severe atrophy and inflammation. To our surprise, the wound healed rapidly with resolution of the tumors and inflammation. In our second patient, the large BCC was located in a cosmetically and functionally critical area of the face. Disfigurement would be inevitable even if the tumor were excised by tissue-sparing micrographic surgery fol­lowed by reconstructive surgery. The two cases illustrated that modern fractionated radiation therapy can be an effective alterna­tive to surgery with good cosmetic results in treating large, disfig­uring facial tumors.

Yi-Pei Lee, J. Yu-Yun Lee* Department of Dermatology, National Cheng Kung University, College of Medicine and Hospital, Tainan, Taiwan

Helen H.W. Chen

Department of Radiation Oncology, National Cheng Kung University, College of Medicine and Hospital, Tainan, Taiwan

Tak-Wah Wong

Department of Dermatology, National Cheng Kung University, College of Medicine and Hospital, Tainan, Taiwan

Forn-Chia Lin, Yuan-Hua Wu

Department of Radiation Oncology, National Cheng Kung University, College of Medicine and Hospital, Tainan, Taiwan

* Corresponding author. J. Yu-Yun Lee, 138 Sheng-Li Road, Tainan, Taiwan Tel.: +886 6 2004326; fax: +886 6 2766180.

E-mail address: yylee@mail.ncku.edu.tw (J.Y.-Y. Lee)

References

1.  Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and other cutaneous entities. J Med Imaging Radiat Oncol 2008;52: 278-86.

2.  de Giorgi V, Sestini S, Campolmi P. Radiotherapy for giant squamous cell carci­nomas. Int J Dermatol 2007;46(5):546-7.

3.  Gkalpakiotis S, Arenberger P, Vohradnikova O, Arenbergerova M. Successful radiotherapy of facial angiosarcoma. Int J Dermatol 2008;47(11):1190-2.

4.  Bath FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell carci­noma of the skin (Cochrane review). Cochrane Database Syst Rev 2007;1: CD003412.

5.  Wilder RB, Kittelson JM, Shimm DS. Basal cell carcinoma treated with radiation therapy. Cancer 1991;68(10):2134-7.

6.  Miller SJ. The National Comprehensive Cancer Network (NCCN) Guidelines of care for nonmelanoma skin cancers. Dermatol Surg 2000;26:289-92.

7.   Liegeois NJ, Seo SJ, Olbricht S. Squamous cell carcinoma. In: Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, editors. Evidence-based dermatology. 2nd ed. London: BMJ Books; 2008. p. 248-55.

8.   Bath-Hextall F, Perkins W. Basal cell carcinoma. In: Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, editors. Evidence-based dermatology. 2nd ed. London: BMJ Books; 2008. p. 256-71.

9.   Neville JA, Welch E, Leffell DJ. Management of nonmelanoma skin cancer in 2007. Nat Clin Pract Oncol 2007;4:462-9.

10. Hernández-Machin B, Borrego L, Gil-García M, Hernández BH. Office-based radiation therapy for cutaneous carcinoma: evaluation of 710 treatments. Int J Dermatol 2007;46:453-9.

Received: Jan 17, 2011 Revised: May 5, 2011 Accepted: May 10, 2011

DERMATOLOGICA SINICA xxx (2014) 1-5

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Dermatologica Sinica

journal homepage: http://www.derm-sinica.com

ORIGINAL ARTICLE

Portable ultraviolet light A1 light source to treat hypertrophic scar

Yen-Chen Huang ¹’², Chin-Te Huang ¹, Chieh Hu ², Tak-Wah Wong ¹’³’ [1]

¹  Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

²  Additive Manufacturing and Laser Application Center, Industrial Technology Research Institute, South Campus, Tainan, Taiwan

³  Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

ABSTRACT

Background/Objectives: Recently, fibrotic diseases such as hypertrophic scar, keloid, and scleroderma have been treated with UV-A1 radiation with encouraging results. However, conventional UV light sources are bulky and expensive. In this study, we aimed to verify the effectiveness of a portable UV-A1 radiation device in treating hypertrophic scars.

Materials and methods: A light-emitting diode array that emitted 365 ± 5 nm (UV-A1) was used to irradiate fibroblasts and hypertrophic scar in a rabbit model.

Results: In cell cultures, UV-A1 light exposure inhibited post-wound cell migration and reduced the total amount of soluble collagen production in fibroblasts. Type I collagenase production and its activity increased after treatment. On the rabbit ear, UV-A1 light irradiation reduced the thickness of hyper­trophic scars, confirming the antifibrotic effect in vivo.

Conclusion: These results support the potential of a portable UV-A1 light device in treating hypertrophic scar.

Copyright © 2014, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Fibrotic diseases in humans, including lung fibrosis,¹ liver cirrhosis,² scleroderma,³ and keloid,^4-6 occur as a result of depo­sition of collagen in tissues or organs due to an imbalance of fibrogenesis and fibrolysis. No effective cure is available to treat these fibrotic diseases. Immunosuppressive agents are usually recommended but they may have significant adverse effects.¹ For skin fibrosing diseases, a safer and effective treatment is UV irra­diation. UV-A light is an electromagnetic radiation with a wave­length of 320-400 nm. Phototherapy with UV-A to treat different skin diseases is usually accompanied by a systemic or topical photosensitizer to enhance the efficacy of the irradiation.⁷ The development of a lamp emitting radiation predominantly in the long-wavelength UV-A1 (340-400 nm), was described in 1981.⁸

High-dose-UV-A1 irradiation without photosensitizer emerged a decade later to treat atopic dermatitis.^9,10

Hypertrophic scars and keloid result from excessive extracel­lular matrix deposition in the dermis after wound healing.⁶ Hy­pertrophic scars are limited to the wound area and usually resolve spontaneously with time. Keloid is defined as scar tissues growing beyond original wounds and is challenging to treat. Large scars may cause disfiguration and loss of function due to scar contracture. Both scars may be complicated with pruritus and pain.¹¹ Traditional scar treatments include pressure garments, silicone gel sheeting, silicone cream and gel, local steroid injection, and excision and repair with/without skin graft and/or radiation.^5,12 Pressure gar­ments are inconvenient and uncomfortable especially in tropical and subtropical countries due to humid and hot weather. Surgical removal of keloid, although temporarily rewarding, is almost invariably followed by even more aggressive regrowth of scar tis- sue.¹² The combination of radiation and surgery provides a higher success rate to cure keloid. However, long-term safety has not been established and invasive tumor may develop after this regimen.¹³ Intralesional steroid injections are probably the most common therapy clinically. Many patients are reluctant to undergo this painful therapy, especially for children and patients with large keloid.^5,14 Recently, UV-A1 has been used in treating localized¹⁵ and generalized scleroderma¹⁶ with encouraging results. UV-A1

http://dx.doi.org/10.1016/j.dsi.2014.10.001

1027-8117/Copyright © 2014, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.

Y.-C. Huang et al. / Dermatologica Sinica xxx (2014) 1—5

irradiation has been shown to stimulate collagenase production by human fibroblasts in vitro.¹⁷ Asawanonda et al¹⁸ demonstrated that UV-A1 with a cumulative dose of 2860J/cm² was helpful in treating keloid in a 37-year-old man. The results were not supported in a subsequent study in which three keloid patients showed no response after receiving UV-A1 irradiation with cumulative doses of 1500—1800 J/cm².¹⁹ Moreover, the application of UV-A1 therapy is limited to a few centers because of the large size and high cost of the machines.²⁰

To develop the application of UV therapy for larger groups of patients, smaller and more economical UV devices are in demand. One potential candidate is the light-emitting diode (LED) light source which has the advantages of portability, high luminance, a relatively narrow spectrum, long lifespan, and low cost. In fact, LEDs in the visible spectrum have been applied to phototherapy in several other skin diseases such as wound healing,²¹ acne,²² and photodynamic therapy.²³ In this study, we tested the efficacy of UV- A1 LEDs in treating hypertrophic scar on rabbit ear.

Materials and methods UV-A1-LED light source

A commercial UV-A1-LED light source (Figure 1B) composed of 18 LEDs (LH365BG02) in a 5-cm circle was bought from Clearstone

Technologies Inc. (Hopkins, MN, USA). This device emits wave­lengths of 365 ± 5 nm with a total optical power of 2500 mW. The uniformity and intensity of light was confirmed by an UV-A meter (UV-Meter HighEnd, Hoenle UV Technology Inc., Grafelfing, Ger­many). The light intensity was set at 30 mW/cm² for in vitro and 100 mW/cm² for in vivo experiments by adjusting the distance from the light source to the treated surface. An electric fan was used to disperse heat during irradiation.

Cells

Human fetal skin fibroblasts (WS1) were obtained from the Bio­resource Collection and Research Center (BRCB, Taipei, Taiwan) and were maintained in Eagle’s Minimum Essential Medium supple­mented with 10% fetal bovine serum, 2.5 mM HEPES, and 100 U/mL penicillin/streptomycin at 37°C in 5% CO₂.

UV-A1 phototoxicity in fibroblasts

The purpose of the study was to determine the optimal UV-A1 dose to inhibit scar formation without damaging cells. The phototoxicity of UV-A1 in fibroblasts was determined by exposing cells to different UV doses after seeding 1 x 10⁴ cells in 100 mL medium per well of a 96-well plate for 16 hours. Cell survival was determined with WST-1 assay²⁵ 24 hours after treatment. The irradiation dose
that was not phototoxic to cells was selected for further experiments.

Total collagen, collagenase I production, and collagenase activity

Supernatant was collected 24 hours after treating cells with UV-A1. Total soluble collagen content in the supernatant was measured with Sircol assay (Biocolor Ltd., Carrickfergus, Antrim, UK).²⁶ Since type I collagen is overproduced in keloid and hypertrophic scar,⁶ we measured type I collagenase (MMPI)²⁶ and its activity²⁷ in the su­pernatant with ELISA kits (Biotrak-ELISA System, Amersham, GE Inc., Piscataway, NJ, USA) following the manufacturer’s instructions.

cm²) while the scars on the other ear served as a control. The scar thickness was measured with a caliper (Mitutoyo Inc., Kawasaki, Japan) and digital images were recorded and assessed by observers blinded to the study.

Statistical analysis

One-way analysis of variance (ANOVA) was used for multiple group comparisons. Unpaired Student’s t test was used to compare be­tween two groups. Dose dependence was analyzed by linear regression. At least two separate independent experiments in triplicate were done for the in vitro studies. A p value <0.05 was considered statistically significant.

Cell migration

Cell migration was assessed by creating a 0.5-mm wound with a 200-mL pipette tip on the center of a confluent cell sheet.²⁷ Cells were treated with mitomycin C (10 mg/mL) to inhibit cell prolifer­ation for 2 hours at 37° C and 5% CO₂ prior to scratching the cell sheet. The damaged area was recorded over time with a digital camera coupled to a microscope and analyzed with Image-J soft­ware (National Institutes of Health, Bethesda, MD, USA).

UV-A1 effect on hypertrophic scar in rabbit ear

Five full-thickness dermal wounds were created on the ventral site of each ear of three New Zealand white rabbits (3—6 months of age,

2—        2.5 kg) with a 6-mm punch.²⁸ All study protocols were in compliance with and approved by the Animal Center Review Board of the institution. Wounds were left open and hypertrophic scars formed in 28 days. Scars on one ear were irradiated every 2 days with 150 J/cm² at 100 mW/cm² UV-A1 for 30 days (total: 2250 J/

UV-A1 inhibits collagen production and enhances collagenase I secretion

As expected,²⁹ the phototoxicity of UV-A1 on human fibroblasts was dose dependent (Figure 2A), with a lethal dose beginning at 9 J/ cm². We therefore adopted UV light doses <9 J/cm² in the rest of the experiments. The main product of fibrosis, the total collagen con­tent, was reduced by UV-A1 irradiation (40% at 3 J/cm², p < 0.05; 70% at 6 J/cm², p < 0.001, one-way ANOVA; Figure 2B). UV-A1 irradiation enhanced collagenase I production in a dose- dependent manner (Figure 2C) and improved the enzyme activity significantly (Figure 2D). The collagenase I in the supernatant increased 33% at 3 J/cm² and 44% at 6 J/cm² compared to the control (p < 0.05, one-way ANOVA; Figure 2C). The enzyme activity increased 25% at 3 J/cm² (p < 0.01) and 21% at 6 J/cm² (p < 0.05), respectively (Figure 2D). These results demonstrated the anti- fibrotic effects of UV-A1.

UV-A1 inhibits migration of fibroblasts

Fibroblast migration may also play a critical role in fibrotic diseases such as active keloid. In the clinic, keloid spreads beyond the margins of the original wound. The fibroblasts proliferate, migrate, and lay down collagen on their path and generate tongue-like fibrotic tissue advancing edges under the microscope.⁴ Fibroblast migration induced by an artificial wound in culture was similarly inhibited in a dose-dependent manner by UV-A1 irradiation (Figure 3).

Rabbit ear scarring is inhibited by UV-A1 irradiation

On the rabbit ear, the minimal dose of UV radiation producing er­ythema was 150—200J/cm² (data not shown). We therefore chose 150 J/cm² to test the effect on the scar (n = 15). After multiple treatments (irradiation every 2 days, cumulative dose 2250 J/cm²), scar tissue became thinner on Day 20 after the onset of irradiation and the change of thickness became statistically significant on Day 84 (Figure 4). The treated scars continued to resolve even after UV therapy was discontinued. The time course of the responses observed in this study (35—84 days after onset of treatment) was consistent with the slow response of fibrotic tissues to other forms of treatment.⁵

A                   0 J/cm2                    3 J/cm2                     6 J/cm2 Figure 3 Effects of UV-A1 on fibroblast migration. Fibroblasts were exposed to different UV-A1 doses after a wound was created on the center of the cell sheet. Cell migration was inhibited by UV-A1 irradiation in a dose-dependent manner (A). Data are mean ± standard error of three separate experiments performed in triplicate (*p < 0.05) (B).

A                                                                  B

Day 0 Day 4 Day 20 Day 28 Day 84 Day 112 Figure 4 Efficacy of UV-A1 irradiation on hypertrophic scars. Five hypertrophic scars were created on each ear in three New Zealand white rabbits. Control scar (A) was hypertrophic while treated scars were reduced in thickness (B) after treatment. The p value was <0.05 compared to the control at 84 days and 112 days after wounding (C). Bar = 6 mm.

Discussion

Our study demonstrates the beneficial effects of LED UV-A1 irra­diation on hypertrophic scar. The efficacy of this small portable, inexpensive LED light source on treating fibrosis tissue is compa­rable to a large UV-A1 machine.¹⁸ Various UV-A1 sources are available, such as fluorescent lamp cubicles which allow only low (10—30 J/cm²) to medium (40—70 J/cm²) individual treatment doses to be administered. High-output metal halide sources allow high doses (up to 130 J/cm²) for a single treatment session. Low and medium UV-A1 dose shows minimal to moderate effects in treating atopic dermatitis, and high UV-A1 dose provides better control of the disease. High UV-A1 dose is particularly promising for localized scleroderma including widespread, pansclerotic, and linear mor­phea because there is no reliable treatment available.³⁰ Setge et al³¹ showed that a high dose (130 J/cm² for 30 times, cumulative dose 3900 J/cm², n = 10) was more effective than a low dose (20 J/cm², cumulative dose 600J/cm², n = 7) of UV-A1 in treating 17 patients with localized scleroderma. Four of 10 patients in the high-dose group showed complete clearance. A higher UV-A1 dose is also required for treating keloid.¹⁸ The higher dose required for treating fibrosing diseases suggests the existence of one effective threshold dose of UV-A1 irradiation, probably higher than 2250 J/cm². The thicker collagenous tissue may need a higher light dose to achieve therapeutic results. It is also likely that an optimal dose may exist along with a temporal course of treatment in relation to the onset time of scar tissue. In the present study, hypertrophic scar was treated after it was established. Whether early UV-A1 intervention prevents hypertrophic scar formation or enhances wound healing remains to be explored.

This rabbit scar model parallels hypertrophic scar in humans and has been used to study potential therapeutic modalities.²⁸ However, the model cannot study the safety of chronic UV-A1

therapy.⁹ Patient data on safety such as carcinogenic effects need to be determined before extensive use of UV-A1 on humans.^9,30 The major acute adverse effects of UV-A exposure are erythema and pigmentation. The erythema response can be avoided by giving a minimal erythema dose test before treatment and adjusting doses according to the response. Pigmentation of the skin is reversible. The major potential chronic adverse effects are photoaging and skin cancer.^32,33 Although it is unclear whether or not UV-A1 increases the risk of melanoma, a case of cutaneous melanoma diagnosed after 18 months intensive UV-A1 and psoralen UV-A (PUVA) for urticaria pigmentosa has been reported. In this report, the total dose of UV-A1 was 910 J/cm², while the total dose of PUVA was 2144J/cm². A role for UV-A in causing malignant melanoma cannot be excluded.³⁴ However, UV-A irradiation causing skin cancer is not detected in persons who are pigmented, tan easily, or are of Asian or African ancestry (Fitzpatrick Skin Type IV or higher). The effec­tive cumulative dose of UV-A1 required for treating keloid in our study was ~2000J/cm² without psoralen. This treatment may be relatively safe in our population. Similarly, the risk of UV-A1 inducing non-melanoma skin cancers, particularly squamous cell carcinoma, is not known, although UV-A induces squamous cell carcinoma-like tumors in mice.³² Another limitation of our study was the lack of fibroblasts from human hypertrophic scar for mechanistic studies. Nevertheless, WS1 fibroblasts are a commer­cial cell line derived from 12-week gestation fetal skin. These cells are highly proliferative and senescent around 70 passages. It has been widely used as a model in wound healing studies.³⁵ Hyper­trophic scar, unlike keloid, usually spontaneously resolves with time. In case of limited resources of human tissue, using WS1 fi­broblasts may be an alternative model.

In summary, we showed in in vitro and in vivo systems that UV- A1 irradiation using an LED light source was effective in treating hypertrophic scars. However, the long-term side effects need to be explored in future experiments.

Acknowledgments

We thank Professor Paul Poon for comments, Prof. Iain C. Bruce, Ms. Stephanie Tsao for reading the manuscript, and Ms. Shu-Fen Ko for technical assistance. The work was supported by Taiwan National Science Council grant 1002314B006018MY2 to T.-W.W.

References

1.   Nagai S, Handa T, Kim D. Pharmacotherapy in patients with idiopathic pul­monary fibrosis. Expert Opin Pharmacother 2008;9:1909—25.

2.   Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838—51.

3.   Chung L, Lin J, Furst DE, Fiorentino D. Systemic and localized scleroderma. Clin Dermatol 2006;24:374—92.

4.   Lee JY, Yang CC, Chao SC, Wong TW. Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol 2004;26:379—84.

5.   Wong TW, Chiu HC, Chang CH, Lin LJ, Liu CC, Chen JS. Silicone cream occlusive dressing—a novel noninvasive regimen in the treatment of keloid. Dermatology 1996;192:329—33.

6.   Ehrlich HP, Desmouliere A, Diegelmann RF, et al. Morphological and immu­nochemical differences between keloid and hypertrophic scar. Am J Pathol 1994;145:105—13.

7.   Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med 1974;291:1207—11.

8.    Mutzhas MF, Holzle E, Hofmann C, Plewig G. A new apparatus with high ra­diation energy between 320-460 nm: physical description and dermatological applications. J Invest Dermatol 1981;76:42—7.

9.    KrutmannJ, Czech W, Diepgen T, Niedner R, Kapp A, Schopf E. High-dose UVA1 therapy in the treatment of patients with atopic dermatitis. JAm Acad Dermatol 1992;26:225—30.

10.   Gambichler T, Terras S, Kreuter A. Treatment regimens, protocols, dosage, and indications for UVA1 phototherapy: facts and controversies. Clin Dermatol 2013;31:438—54.

11.   Wong TW, Lee JY, Sheu HM, Chao SC. Relief of pain and itch associated with keloids on treatment with oxpentifylline. Br J Dermatol 1999;140:771—2.

12.   Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scar­ring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med 2011;17:113—25.

13.   Fish LM, Duncan L, Gray KD, Bell JL, Lewis JM. Primary cutaneous melanoma arising in a long-standing irradiated keloid. Case Rep Surg 2012;2012:165319.

14.   Chen YH, Wong TW, Sheu HM, Tsai JC, Li SF. Iontophoretic local anesthesia to ameliorate painful intralesional injection in treating keloid. Dermatol Sinica 2001;19:1—7.

15.   Gruss C, Reed JA, Altmeyer P, McNutt NS, Kerscher M. Induction of interstitial collagenase (MMP-1) by UVA-1 phototherapy in morphea fibroblasts. Lancet 1997;350:1295—6.

16.   von Kobyletzki G, Uhle A, Pieck C, Hoffmann K, Altmeyer P. Acrosclerosis in patients with systemic sclerosis responds to low-dose UV-A1 phototherapy. Arch Dermatol 2000;136:275—6.

17.   Wefers H, Melnik BC, Flur M, Bluhm C, Lehmann P, Plewig G. Influence of UV irradiation on the composition of human stratum corneum lipids. J Invest Dermatol 1991;96:959—62.

18.   Asawanonda P, Khoo LS, Fitzpatrick TB, Taylor CR. UV-A1 for keloid. Arch Dermatol 1999;135:348—9.

19.   Hannuksela-Svahn A, Grandal OJ, Thorstensen T, Christensen OB. UVA1 for treatment of keloids. Acta Derm Venereol 1999;79:490.

20.   Kerr AC, Ferguson J, Attili SK, et al. Ultraviolet A1 phototherapy: a British Photodermatology Group workshop report. Clin Exp Dermatol 2012;37: 219—26.

21.   Al-Watban FA, Andres BL. Polychromatic LED in oval full-thickness wound healing in non-diabetic and diabetic rats. Photomed Laser Surg 2006;24:10—6.

22.   Lee SY, You CE, Park MY. Blue and red light combination LED phototherapy for acne vulgaris in patients with skin phototype IV. Lasers Surg Med 2007;39: 180—8.

23.   Wong TW, Sheu HM, Lee JY, Fletcher RJ. Photodynamic therapy for Bowen's disease (squamous cell carcinoma in situ) of the digit. Dermatol Surg 2001;27: 452—6.

24.   Houreld N, Abrahamse H. Irradiation with a 632.8 nm helium-neon laser with 5 J/cm2 stimulates proliferation and expression of interleukin-6 in diabetic wounded fibroblast cells. Diabetes Technol Ther 2007;9:451—9.

25.   Bogdanovic G, Kojic V, Dordevic A, Canadanovic-Brunet J, Vojinovic- Miloradov M, Baltic VV. Modulating activity of fullerol C60(OH)22 on doxorubicin-induced cytotoxicity. Toxicol In Vitro 2004;18:629—37.

26.   Keyszer G, Lambiri I, Nagel R, et al. Circulating levels of matrix metal- loproteinases MMP-3 and MMP-1, tissue inhibitor of metalloproteinases 1 (TIMP-1), and MMP-1/TIMP-1 complex in rheumatic disease. Correlation with clinical activity of rheumatoid arthritis versus other surrogate markers. J Rheumatol 1999;26:251—8.

27.   Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2007;2:329—33.

28.   Saulis AS, Mogford JH, Mustoe TA. Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plast Reconstr Surg 2002;110:177—86.

29.   Leccia MT, Richard MJ, Favier A, Beani JC. Zinc protects against ultraviolet A1- induced DNA damage and apoptosis in cultured human fibroblasts. Biol Trace Elem Res 1999;69:177—90.

30.   Dawe RS. Ultraviolet A1 phototherapy. Br J Dermatol 2003;148:626—37.

31.   Stege H, Berneburg M, Humke S, et al. High-dose UVA1 radiation therapy for localized scleroderma. J Am Acad Dermatol 1997;36:938—44.

32.   de Laat A, van der Leun JC, de Gruijl FR. Carcinogenesis induced by UVA (365­nm) radiation: the dose-time dependence of tumor formation in hairless mice. Carcinogenesis 1997;18:1013—20.

33.   Epstein JH. Photocarcinogenesis, skin cancer, and aging. J Am Acad Dermatol 1983;9:487—502.

34.   Wong TW, Lee JY. Should excised keloid scars be sent for routine histologic analysis? Ann Plast Surg 2008;60:724.

35.   Houreld NN, Ayuk SM, Abrahamse H. Expression of genes in normal fibroblast cells (WS1) in response to irradiation at 660nm. J Photochem Photobiol B 2014;130:146—52.

DERMATOLOGICA SINICA 31 (2013) 68-72

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BRIEF REPORT

Secondary intention healing with satisfactory outcome after nodular basal cell carcinoma excision on the face

Jia-Ming Yeh¹, Chun-Yen Ou², Julia Yu-Yun Lee¹, Tak-Wah Wong^1,3,[2]

¹ Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan ²Department ofOtolaryngology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

³ Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

ARTICLE INFO

Secondary intention healing on concave areas of the face may provide acceptable cosmetic outcome after tumor excision but is underused. We evaluated cosmetic outcome and tumor recurrence of this technique in 10 patients with nodular basal cell carcinoma and one patient with basosquamous carci­noma on the face. The average size of these tumors was 1 cm. Subjective evaluations included patients' satisfaction on the degree of wound pain, ease of wound care, and satisfaction with cosmetic outcome. Objective evaluations included physician's scoring on the time to complete wound healing, wound infection, cosmetic outcome, and tumor recurrence after operation. The operations were completed in 30 minutes on average. All wounds healed well without infection within 4 weeks. Postoperation wound pain was absent to mild. Wound care was neither difficult nor troublesome. All patients were satisfied with the cosmetic outcome. Physicians scored good or excellent cosmetic outcome in 91% of patients. No tumor recurred during 3—60 months (median, 13 months) of follow-up. Secondary intention healing appears to be a good option after excision of nodular basal cell carcinomas located on concave areas of the face. Good to excellent cosmetic results can be expected after wound healing.

Copyright © 2012, Taiwanese Dermatological Association.

Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Surgical removal of cutaneous neoplasms from the head and neck region creates a variety of cutaneous defects requiring tissue reconstruction. The ideal reconstruction of skin defects aims to close the defects with good cosmesis and without morbidity. Wound reconstruction techniques include primary closure; healing by secondary intention; skin grafts; and local, regional, and sometimes free flaps. The choice of reconstruction method often depends on the preference and experience of the surgeon and patients’ expectations.

Healing by secondary intention offers the advantages of optimal cancer surveillance, simplified wound management, and avoidance of sophisticated reconstructive procedures. In the early days of tumor removal using Mohs' fixed tissue technique, most of the surgical wounds were allowed to heal by secondary intention.¹

Although there are many reports on secondary intention healing (SIH) in the literature, data with a sound statistical basis are limited.^2,3 In 1983, Zitelli⁴ reviewed facial defects managed by SIH comprehensively and found that the anatomic location of surgical wounds was the most important predicting factor for the cosmetic outcome (Figure 1). Wounds located on the concave surfaces of the nose, eye, ear, and temple areas usually heal with functional and cosmetic outcomes that equal or are superior to those achieved by grafts and flap transpositions.^4—6 However, SIH is usually under­used after surgery. In this study, we evaluated SIH in 11 patients with basal cell carcinoma on the face.

Patients and methods Patients

All facial reconstructions after tumor excision that healed with SIH in one medical center between 1990 and 2010 were reviewed. Photos of patients before and after operation were reviewed from a database (Crux system) of the department. Eleven patients, eight males and three females, aged 57—86 years (mean age, 73 years), with nonmelanoma skin cancers on the face were included

Figure 1 Acceptable cosmetic outcome of secondary intention healing on a particular anatomic area of the face. The location of tumors in our patients (red spots) is shown on the figure. Note. From “Wound healing by secondary intention: a cosmetic appraisal” by JA Zitelli, 1983. J Am Acad Dermatol 9, p 407—15. Adapted with permission.

(Table 1). All tumors were basal cell carcinoma except for one basosquamous carcinoma that was confirmed histopathologically. The tumors of 10 patients were located on the concave areas of the face and one patient’s tumor was on the convex area (Figure 1). The sizes of the tumors ranged from 0.3 to 3 cm (average, 1 cm) and were noted for 4 months to 10 years (mean, 2.8 years) by the patients before operation. The benefits and risks of SIH were well explained to patients before surgery.

Secondary intention healing

The facial tumors were excised with adequate free margins, usually

3—   
5 mm. The skin defect after tumor excision ranged from 1.3 to 4 cm. Primary closure or closure by skin graft or flap were considered to be less ideal than SIH. All patients were instructed to change the wound dressing once daily with topical antibiotic ointment after gentle cleansing with normal saline, and then cover the wound with gauze. All patients were prescribed oral cephalexin and acetaminophen four times daily for 1 week after operation.

The subjective evaluations included degree of wound pain (none, mild, moderate, and severe); ease of wound care (easy, fair, difficult, and troublesome); and satisfaction with cosmetic outcome (satisfied or not satisfied). Objective evaluations, including time to complete wound healing, wound infection, tumor recurrence, and cosmetic outcome with photographs using a categorical judgment

scale (poor, average, good, and excellent), physicians blinded to the study.

Results

were assessed by two

All patients were followed up 3—65 months (median, 13 months) after surgery (Table 1). All tumors were located at concave areas of the face except for one on the forehead (Figure 2C). One tumor (in patient 4) had been treated with liquid nitrogen spray and one (in patient 5) had been partially excised at another clinic.

The operation was completed in 30 minutes on average. The wounds needed 2—6 weeks (average, 4 weeks) to heal completely. No recurrence of tumor was found during 3—65 months’ (mean, 22.3 months) follow-up.

Postoperative wound care was neither difficult nor troublesome for all patients (easy in two patients [18.2%] and fair in nine patients [81.9%]). Analgesic agents other than acetaminophen was not required because there was no wound pain in seven patients (63.3%) and only mild pain in four patients (36.4%). No wound infection was observed and all patients were satisfied with the cosmetic outcome. Objective cosmetic outcome was good to excellent in 91% of patients (good, 77.3%; excellent, 13.6%) (Figure 2). In particular, patient 10 had two facial tumors. The tumor on the left nasofacial sulcus was excised earlier and the wound was closed with primary closure, which resulted in mild nostril deformity. The tumor on the left nasolabial fold was left to SIH. Both the patient and surgeon were more satisfied with the cosmetic result of SIH (Figure 3).

Discussion

We reported the success and satisfactory results of SIH in a series of patients with basal cell carcinoma of the face after excision. In the current era of elegant and elaborate reconstructive techniques, SIH is often underutilized. However, under certain circumstances, SIH can offer functional and cosmetic outcomes that equal or are superior to those achieved by primary closure, grafts, and flaps.^4—6 This simple reconstructive method allows optimal wound bed
surveillance for tumor recurrence with a low complication rate, and the avoidance of complex procedures in patients who are at risk of long operation time.⁸ However, SIH in anatomic areas with high contractile forces, such as eyelid margins and eyebrow and lip vermilion borders, may result in retraction of free tissue margins. Thus, this technique is not recommended in these anatomic areas. Disadvantages of SIH include prolonged healing time, the need for daily wound care, and occasionally unpredictable cosmetic results.^9,10 The cosmetic outcome can only be assessed after complete wound healing.

There are some factors to consider when choosing patients for SIH. Location is probably the most important predictive factor for the esthetic outcome SIH.^4,11 Wound contraction is usually more favorable in concave areas. The extent of wound contraction depends on the initial wound size and is positively correlated with the degree of surface concavity, adjacent skin laxity, and the
action of underlying skeletal muscles.¹² The favorable outcome in our patients may relate to relatively small tumor sizes in our series (average, 1 cm). A small wound (<1 cm) can heal more than 70% by wound contracture with acceptable cosmetic outcome in comparison with a larger wound (>2.5 cm in diam­eter).^13,14 A superficial defect, even on a convex surface, may also heal with acceptable cosmesis as illustrated by the wound on the forehead in patient 3 (Figure 2C).^4,15 Aged skin (in patients with mean age 73 years) may be another factor attributed to a more favorable outcome in our patients. Skin in elderly patients is more relaxed and the presence of irregular contour and pigment can readily camouflage operation scars. Indeed, several authors suggested that elderly patients are better candidates for SIH.⁵,⁸,¹⁴,¹⁵

The traditional wound dressing for an incisional wound contains three layers — a nonadhering layer in contact with the wound, an absorptive layer that absorbs wound exudates, and a binding layer to fix the dressing in place.¹⁶ However, the dressings may be too bulky and cumbersome for patients and the relatively dry environment is not optimal for wound healing. An occlusive or semiocclusive dressing that provides a moist healing environment is believed to facilitate wound healing by accelerating reepithelialization and minimizing desiccation, necrosis, and pain.^16,17 For our patients, the goal was a simple wound dressing that could be done by the patient at home. We educated the patients on how to clean the wound with normal saline and cover with gauze after filling the wound with antibiotic ointment. The ointment provides a semiocclusive environment for the wound. Indeed, all wounds healed without complications within 4 weeks.

In conclusion, our results suggest that SIH is a simple technique for wound closure after excision of nodular basal cell carcinoma if the wound is smaller than 2.5 cm and located over concave areas of the face. In such clinical settings, SIH proved to be an alternative for wound closure, with good to excellent cosmetic results.

Acknowledgments

The study was supported by the National Science Council of Taiwan grants NSC992627E033001 and NSC1002627E033001 to Dr Tak- Wah Wong.

References

1.   Mohs FE. Chemosurgery for the microscopically controlled excision of skin cancer. J Surg Oncol 1971;3:257—67.

2.   Mohs FE. Chemosurgery. Clin Plast Surg 1980;7:349—60.

3.   Shriner DL, McCoy DK, Goldberg DJ, Wagner Jr RF. Mohs micrographic surgery. J Am Acad Dermatol 1998;39:79—97.

4.   Zitelli JA. Secondary intention healing: an alternative to surgical repair. Clin Dermatol 1984;2:92—106.

5.   Moscona R, Pnini A, Hirshowitz B. In favor of healing by secondary intention after excision of medial canthal basal cell carcinoma. Plast Reconstr Surg 1983;71:189—95.

6.   Bernstein G. Healing by secondary intention. Dermatol Clin 1989;7:645—60.

7.   van der Eerden PA, Lohuis PJ, Hart AA, et al. Secondary intention healing after excision of nonmelanoma skin cancer of the head and neck: statistical evaluation of prognostic values of wound characteristics and final cosmetic results. Plast Reconstr Surg 2008;122:1747—55.

8.   Goldwyn RM, Rueckert F. The value of healing by secondary intention for sizeable defects of the face. Arch Surg 1977;112:285—92.

9.   McGrath MH, Simon RH. Wound geometry and the kinetics of wound contraction. Plast Reconstr Surg 1983;72:66—73.

10.  Cordoro KM, Russell MA. Minimally invasive options for cutaneous defects: secondary intention healing, partial closure, and skin grafts. Facial Plast Surg Clin North Am 2005;13:215—30. v.

11.  Diwan R, Tromovitch TA, Glogau RG, Stegman SJ. Secondary intention healing. The primary approach for management of selected wounds. Arch Otolaryngol Head Neck Surg 1989;115:1248—9.

12.  Hinrichsen N, Birk-Sorensen L, Gottrup F, Hjortdal V. Wound contraction in an experimental porcine model. Scand J Plast Reconstr Surg Hand Surg 1998;32:243-8.

13.  Mott KJ, Clark DP, Stelljes LS. Regional variation in wound contraction of mohs surgery defects allowed to heal by second intention. Dermatol Surg 2003;29: 712-22.

14.  Lawrence CM, Comaish JS, Dahl MG. Excision of skin tumours without wound closure. Br J Dermatol 1986;115:563-71.

15.  Zitelli JA. Wound healing by secondary intention: a cosmetic appraisal. J Am Acad Dermatol 1983;9:407-15.

16.  Lionelli GT, Lawrence WT. Wound dressings. Surg Clin North Am 2003;83:617-38.

17.  Dziewulski P, James S, Taylor D, et al. Modern dressings: healing surgical wounds by secondary intention. Hosp Med 2003;64:543-7.

DERMATOLOGICA SINICA 32 (2014) 90-92

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CASE REPORT

In situ photoimmunotherapy is ineffective in treating deeply invasive squamous cell carcinoma

Tak-Wah Wong^1,2,3,[3], Stephanie Tsao⁴, Julia Yu-Yun Lee¹

¹ Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

² Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

³ Research Center of Wound Regeneration and Repair, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

⁴ Department of Biology, Marshall College, University of California San Diego, La Jolla, CA, USA

ABSTRACT

In situ photoimmunotherapy (ISPI) can be a treatment option for selected cutaneous malignancies in patients who are not surgical candidates. We herein report the case of a large, ulcerating poorly differentiated squamous cell carcinoma (SCC) affecting the foot of an elderly woman with chronic arsenicosis. The tumor failed radiotherapy, intralesional methotrexate, and 5-aminolevulinic acid photodynamic therapy (PDT). Because the patient was reluctant to undergo amputation, the recurrent tumor was treated with ISPI using topical imiquimod application followed by PDT. Despite some initial improvement 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 arsenicosis is believed to be more invasive.¹ The treatment of choice is surgical excision.² However, alternative treatments may be needed for pa­tients who cannot tolerate or refuse surgery. Imiquimod is a topical immune modifier acting mainly by exhibiting agonistic activity toward Toll-like receptors 7 and 8.³ Initially, it was approved to treat genital and perianal warts. In recent years, imiquimod has been used as a safe and effective treatment option for a variety of skin cancers including actinic keratosis, basal cell carcinoma, SCC in situ (Bowen’s disease), lentigo maligna, and extramammary Paget’s disease.⁴ Although studies of imiquimod in treating invasive SCC are limited, some case reports showed encouraging outcomes.^5-7 For example, Hengge and Schaller⁵ treated a 65-year-old man with a 4 cm x 3 cm SCC on the temple area. The tumor was treated by applying 5% imiquimod cream overnight three times a week. At week 16, the tumor was cured completely, which was also confirmed by a histopathological analysis. There was no tumor recurrence at the 16-month follow-up examination.⁵

Photodynamic therapy (PDT) destroys tumor cells by activating a photosensitizer by a specific wavelength of light after selective accumulation of the photosensitizer in cancer cells.⁸ In situ pho­toimmunotherapy (ISPI), which comprises PDT and topical imi- quimod, has shown promising results in patients with highly aggressive cancers including metastatic melanoma^9,10 and angio- sarcoma.¹¹ A patient with cutaneous metastasizing melanoma preserved his left foot after ISPI.¹² Although there is no report concerning ISPI in treating invasive SCC, these results encouraged us to treat our patient with ISPI as a limb-sparing approach.

Case report

An 85-year-old female with chronic arsenicosis visited our clinic in 2005 with an 8-year history of chronic nonhealing ulcer over her right dorsal foot. A physical examination revealed a large ulcer (7.2 cm x 5 cm; Figure 1A), which proved to be a poorly differen­tiated SCC with minimal dermal invasion histopathologically. She refused surgical intervention or chemotherapy but accepted radi­ation therapy. There was approximately 90% improvement of the tumor (Figure 1B) with re-epithelization after radiotherapy with a total dose of 4000 cGy over 4 months. However, local recurrence with ulceration occurred 3 months later. Both the radiologist and surgeon suggested amputation but the patient refused. She preferred less invasive approaches, such as local chemotherapy and/or PDT. Since then, she has received weekly or biweekly in­jections 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 acid for 6 hours prior to exposing it to 120 J/cm² at 120 mW/cm² red light (PDT 1200 lamp; Waldmann, Villingen-Schwenningen, Ger­many).¹³ The ulcer showed a partial response (Figure 1C) after she received 62 mg methotrexate and 660 J/cm² over 4 months, but it relapsed soon after. In an attempt to stimulate host immune response against the tumor, 250 mg (5%) imiquimod cream (Aldara; 3M Pharmaceuticals, St. Paul, MN, USA) was evenly applied on the ulcer, which was subsequently occluded with an air-permeable water-resistant membrane (Tegaderm; 3M Pharmaceuticals) for 12 hours daily over 12 days. One additional PDT (120 J/cm²) was performed on Day 6 during imiquimod therapy. She tolerated the treatments well and the tumor improved clinically (Figure 1D). Regrettably, a follow-up radiographic examination showed evi­dence of tumor invasion to the underlying metatarsal bone, which was intact 5 months prior to ISPI (arrows, Figure 1E and F). She finally underwent below the knee amputation and was disease free at 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 arsenic exposure and HPV seropositivity were associated with increased nonmelanoma skin cancer risks.¹⁴ However, the mechanisms by which HPV and arsenic interact remain to be established. Even though we did not examine HPV titer in this patient, it is of interest to investigate the role of HPV in skin cancer arising in patient with chronic arsenicosis.

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

ISPI is a new anticancer therapy, which intends to boost the host immune response against cancer. This is achieved by the activation of innate and cellular immune responses with imiquimod when tumor antigens have been generated by tumor cell destruction with PDT.³ The tumor antigens are strong and specific. A systemic im­mune response specifically against a distant tumor can be elicited by treating a tumor locally with PDT and imiquimod. The failure of ISPI in our patient might be attributed to the following reasons. (1) The tumor was naturally less responsive to ISPI. (2) The absorption peak (635 nm) of the photosensitizer protoporphyrin IX, the active metabolite of 5-aminolevulinic acid, only penetrates the superficial dermis leaving the deeper part of the tumor untouched. By com­parison, the infrared absorption peak of indocyanine green used in treating melanomas can penetrate deeper tissues. The immune responses elicited by ISPI may depend on the dose and strength of the antigens generated from tumor destruction. The insufficient destruction of the tumor might have limited the release of tumor antigens in our patient. It is well known that tumor antigens of malignant melanoma are highly immunogenic. Melanoma- associated vitiligo is the best studied example of the linkage be­tween tumor immunity and autoimmunity.¹⁷ The tumor antigens of SCC released after ISPI might not be as immunogenic as in mela­noma. The patient had three small Bowen’s diseases (SCC in situ) on her trunk. The lesions were treated with cryotherapy and healed without recurrence prior to ISPI. Otherwise, we could observe the systemic effects of ISPI. (3) The amount of imiquimod absorbed might not be sufficient to initiate antitumor immunity. Naylor et al¹⁰ did not quantify the amount of imiquimod they used in ISPI. Nevertheless, they applied 20 cm² x 20 cm² imiquimod on their patient’s skin, an area that was approximately three times larger than our patient.

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

Acknowledgments

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

References

1.   Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344: 975—83.

2.   Belkin D, Carucci JA. Mohs surgery for squamous cell carcinoma. Dermatol Clin 2011;29:161—74. vii.

3.   Schön MP, Schön M. Imiquimod: mode of action. BrJ Dermatol 2007;157:8—13.

4.   Cohen PR, Schulze KE, Tschen JA, Hetherington GW, Nelson BR. Treatment of extramammary Paget disease with topical imiquimod cream: case report and literature review. South Med J 2006;99:396—402.

5.   Hengge UR, Schaller J. Successful treatment of invasive squamous cell carci­noma using topical imiquimod. Arch Dermatol 2004;140:404—6.

6.   Nouri K, O’Connell C, Rivas MP. Imiquimod for the treatment of Bowen’s dis­ease and invasive squamous cell carcinoma. J Drugs Dermatol 2003;2:669—73.

7.   Eklind J, Tartler U, Maschke J, Lidbrink P, Hengge UR. Imiquimod to treat different cancers of the epidermis. Dermatol Surg 2003;29:890—6. discus­sion 896.

8.   Zeitouni NC, Oseroff AR, Shieh S. Photodynamic therapy for nonmelanoma skin cancers. Current review and update. Mol Immunol 2003;39:1133—6.

9.   Li X, Naylor MF, Le H, et al. Clinical effects of in situ photoimmunotherapy on late-stage melanoma patients: a preliminary study. Cancer Biol Ther 2010;10: 1081—7.

10.  Naylor MF, Chen WR, Teague TK, Perry LA, Nordquist RE. In situ photo­immunotherapy: a tumour-directed treatment for melanoma. Br J Dermatol 2006;155:1287—92.

11.  Thong PS, Ong KW, Goh NS, et al. Photodynamic-therapy-activated immune response against distant untreated tumours in recurrent angiosarcoma. Lancet Oncol 2007;8:950—2.

12.  St Pierre SA, Rommel J, Ciurea A, et al. In situ photoimmunotherapy: a surgery- and limb-sparing approach to the treatment of cutaneous metastases in advanced melanoma. Arch Dermatol 2010;146:831—4.

13.  Wong TW, Sheu HM, Lee JY, Fletcher RJ. Photodynamic therapy for Bowen’s disease (squamous cell carcinoma in situ) of the digit. Dermatol Surg 2001;27: 452—6.

14.  Rosales-Castillo JA, Acosta-Saavedra LC, Torres R, et al. Arsenic exposure and human papillomavirus response in non-melanoma skin cancer Mexican pa­tients: a pilot study. IntArch Occup Environ Health 2004;77:418—23.

15.  Goh MS. Invasive squamous cell carcinoma after treatment of carcinoma in situ with 5% imiquimod cream. Australas J Dermatol 2006;47:186—8.

16.  Gong HS, Cho JH, Roh YH, Chung MS, Baek GH. Bone invasion by squamous cell carcinoma in situ (Bowen’s disease) of the finger during treatment with imi- quimod 5% cream: case report. J Hand Surg Am 2010;35:999—1002.

17.  Byrne KT, Turk MJ. New perspectives on the role of vitiligo in immune responses to melanoma. Oncotarget 2011;2:684—94.

DERMATOLOGICA SINICA 28 (2010) 130-132

ELSEVIER                                                                                                                                            CORRESPONDENCE

Spontaneous resolution of recalcitrant generalized prurigo nodularis after resection of an ampulla of Vater tumor

1,2,3*

Yun-Ting Su¹, Julia Yu-Yun Lee¹, Tak-Wah Wong

’Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

²Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan ³Institute of Clinical Medicine, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan

Case report

A 63-year-old retired male teacher presented with general­ized pruritic papules for 4 years. The prurigo was recalci­trant to treatment and he was admitted for further evaluation and treatment. His medical history was significant for thy­roidectomy for hyperthyroidism 23 years ago with normal thyroid function after surgery. He had hyperuricemia with gouty arthritis but received no treatment. He also complained of epigastric discomfort for several decades. He denied any history of atopy or drug allergies, and was not on medica­tions before the onset of skin lesions. A blood examination showed peripheral eosinophilia (1040/mm³). The serum IgE level was within the normal range. There was no hyperbiliru­binemia. A stool examination showed no evidence of para­site infection. After discharge, he received treatment at other clinics in his hometown for 7 years.

In 2001, he returned to our clinic because of worsening of the skin lesions. An examination revealed many licheni- fied and juicy papules disseminated on his trunk and ex­tremities (Figures 1A-1C). A biopsy taken from a lichenoid papule showed compact hyperkeratosis, hypergranulosis, epidermal hyperplasia and fibrotic papillary dermis with di­lated blood vessels, consistent with lichen simplex chronicus or prurigo histopathologically. The diagnosis of generalized prurigo nodularis was made. The prurigo showed a poor response to treatments, including topical high potency ster­oids, oral antihistamines and narrow band UVB phototherapy. New lesions continued to erupt despite 18 months of inten­sive treatments. Follow-up eosinophil counts were within normal limits. The patient finally gave up and declined further

^Corresponding author. Department of Dermatology, National Cheng Kung University Medical College and Hospital, 138 Sheng-Li Rd, Tainan 704, Taiwan.

E-mail: Dr.kentwwong@gmail.com

Received: Jul 27, 2009 • Revised: Oct 5, 2009 • Accepted: Oct 15, 2009

Copyright © 2010, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.

treatments. One year after giving up treatments for prurigo, he underwent an endoscopic retrograde cholangiopancrea­tography to evaluate his epigastric discomfort. It revealed a tumor at the ampulla of Vater, which was shown to be an adenoma pathologically (Figure 2A). Magnetic resonance imaging (Figure 2B) showed a tumor in the ampulla of Vater region. The patient had no signs of cholestasis. His serum levels of bilirubin, amylase and lipase were within the nor­mal range. The tumor was excised and the final pathological diagnosis was villotubular adenoma with moderate dyspla­sia. Surprisingly, the prurigo showed spontaneous improve­ment and disappeared completely 2 years after an operation (Figures 3A-3C). He remained free of prurigo at 4 years follow-up.

Discussion

We report a case with chronic, recalcitrant widespread pru­rigo nodularis that resolved spontaneously after resection of an ampulla of Vater tumor. Adenomas of the ampulla of Vater are rare neoplasms with an incidence of 0.04-0.12% in a postmortem series.¹ The tumor can obstruct normal drain­age of pancreatic or bile secretions and cause jaundice, cholangitis and pancreatitis. More importantly, these ade­nomas have the potential for malignant changes.¹ Patients with adenoma of the ampulla of Vater may complain of non­specific upper abdominal discomfort. Pruritus usually occurs in patients with obstructive jaundice and is relieved by removal of the tumor.²

Prurigo nodularis is characterized by a papulonodular eruption with intense pruritus. Although the acute form is often induced by insect stings, most of the subacute and chronic forms appear to be idiopathic.³ Chronic lesions are usually difficult to treat and cause frustration to both patients and physicians. Prurigo nodularis is sometimes associated with atopy, pregnancy, systemic diseases, malabsorption, or

Figure 1 (A-C)           A 63-year-old              male had progressively worsening generalized prurigo    nodularis.

Figure 2    (A) An endoscopic retrograde cholangiopancreatography for evaluation of patient's chronic epigastric discomfort reveals a tumor at the ampulla of Vater (arrow). (B) Magnetic resonance imaging (T1 phase) shows a tumor in the ampulla Vater region (arrow).

Figure 3    (A-C) The skin lesions were chronic and recalcitrant to various treatments, but resolved spontaneously in 2 years after resection of a

villotubular adenoma with moderate dysplasia of the ampulla of Vater.

malignancy.³ Prurigo nodularis has been reported as an initial presentation of internal malignancies, including hepatocel­lular carcinoma,⁴ metastatic transitional cell carcinoma,⁵ Hodgkin's disease,⁶ adult T-cell leukaemia/lymphoma⁷ and gastric cancer.⁸ Prurigo may represent a paraneoplastic sign of hepatocellular carcinoma in which the skin lesions resolve after tumor removal.⁴ To the best of our knowledge, general­ized prurigo nodularis associated with adenoma of the am­pulla of Vater without obstructive jaundice, as seen in our patient, has never been reported.²

The prurigo lesions in the present case were preceded by chronic upper abdominal discomfort for several decades.

The finding of moderate dysplasia in a villotubular adenoma suggests that the adenoma might have been longstanding and had undergone malignant transformation, and this might be associated with the development of prurigo lesions chronologically.

The mechanism of prurigo in our patient remains elusive. Neuropeptides, including neuronal growth factors, calcitonin gene-related peptide and substance P, have been proposed as the pathogenesis of prurigo nodularis.³ Further study is required to clarify whether the tumor in the present case secreted pruritogenic neuropeptides. Nevertheless, the spon­taneous resolution of the recalcitrant prurigo after tumor excision suggests that there may have been a causal relation­ship between the recalcitrant prurigo nodularis and the ampulla Vater adenoma.

In summary, we report a patient with refractory general­ized prurigo nodularis, which resolved spontaneously after excision of a dysplastic ampulla of Vater tumor. We recom­mend a thorough survey of internal malignancy for patients with recalcitrant prurigo as this may be a sign of internal malignancy on rare occasions, and an ampulla of Vater

tumor should not be overlooked in patients with chronic

epigastric discomfort.

References

1.     Yamaguchi K, Enjoji M. Adenoma of the ampulla of Vater: puta­tive precancerous lesion. Cut 1991;32:1 558-61.

2.     Venu RP, Geenen JE. Diagnosis and treatment of diseases of the papilla. Clin Gastroenterol 1986;15:439-56.

3.     Lee MR, Shumack S. Prurigo nodularis: a review. Australas J Dermatol 2005;46:211-8; quiz 219-20.

4.     Dalle S, Merle P, Gouillat C, et al. Hepatocellular carcinoma revealed by prurigo. Ann Dermatol Venereol 2006;1 33:243-5.

5.     Lin JT, Wang WH, Yen CC„ et al. Prurigo nodularis as initial pres­entation of metastatic transitional cell carcinoma of the bladder. J Urol 2002;168:631-2.

6.     Shelnitz LS, Paller AS. Hodgkin's disease manifesting as prurigo nodularis. Pediatr Dermatol 1990;7:136-9.

7.     Setoyama M, Mizoguchi S, Kanzaki T. Prurigo as a clinical pro­drome to adult T-cell leukaemia/lymphoma. Br J Dermatol 1998; 138:137-40.

8.     Funaki M, Ohno T, Dekio S, et al. Prurigo nodularis associated with advanced gastric cancer: report of a case. J Dermatol 1996; 23:703-7.

Conflicts of interest: The authors declare that they have no financial or non- financial conflicts of interest related to the subject matter or materials discussed in this article.

Conflicts of interest: The authors declare that they have no financial or non- financial conflicts of interest related to the subject matter or materials discussed in this article.

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[1] Corresponding author. Department of Dermatology, National Cheng-Kung University Medical College and Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan.

E-mail addresses: twwong@mail.ncku.edu.tw, Dr.Kentwwong@gmail.com

(T.-W. Wong).

[2] Corresponding author. Department of Dermatology, National Cheng Kung University Medical College and Hospital, No.138, Sheng Li Road, Tainan 704, Taiwan. Tel.: +886 2353535x5352; fax: +886 6 2004326.

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

[3] Corresponding author. Department of Dermatology, National Cheng Kung University Medical College and Hospital, Number 138, Sheng Li Road, Tainan 704, Taiwan. Tel.: 886 6 2353535x5352; fax: 886 6 2004326.

E-mail addresses: Dr.kentwwong@gmail.com, twwong@mail.ncku.edu.tw

(T.-W. Wong).