Lasers Med Sci DOI 10.1007/s10103-014-1686-1
BRIEF REPORT
The effect of pulsed dye laser on high-risk basal cell carcinomas with response control by Mohs micrographic surgery Leticia Alonso-Castro & Luis Ríos-Buceta & Pablo Boixeda & John Paoli & Carmen Moreno & Pedro Jaén
Received: 6 May 2014 / Accepted: 23 October 2014 # Springer-Verlag London 2014
Abstract Several reports have shown the effectiveness of pulsed dye laser (PDL) for the treatment of basal cell carcinoma (BCC). Most studies have focused on low-risk BCCs, but an important limitation has been the lack of histologic confirmation of the treatment results. The aim of this study was to assess the effectiveness of PDL in high-risk BCCs with complete histologic evaluation with Mohs micrographic surgery (MMS). Seven patients with high-risk BCCs located on the face were included. All tumors were treated with three sessions of PDL (595 nm) at 4-week intervals. The tumor and 4 mm of peripheral skin were treated with two stacked pulses with a 1-s delay, a fluence of 15 J/cm2, a pulse duration of 2 ms, and a spot size of 7 mm. MMS was performed at least 1 month after the last PDL session including excisional tumor L. Alonso-Castro (*) : L. Ríos-Buceta : P. Boixeda : J. Paoli : P. Jaén Department of Dermatology, Ramón y Cajal University Hospital, Madrid, Spain e-mail: [email protected] L. Ríos-Buceta e-mail: [email protected] P. Boixeda e-mail: [email protected] J. Paoli e-mail: [email protected] P. Jaén e-mail: [email protected] J. Paoli Department of Dermatology, Sahlgrenska University Hospital, Institute of Clinical Sciences at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden C. Moreno Department of Pathology, Ramón y Cajal University Hospital, Madrid, Spain e-mail: [email protected]
debulking prior to the first stage of MMS for standard histologic evaluation. Apparent complete clinical response was achieved in five of seven patients. MMS was finally performed in six patients, and clear margins were achieved after one stage of MMS. The histologic evaluation of the tumor debulking specimens showed complete clearance in four of six cases. One patient who did not undergo MMS showed a recurrence after 14 months. This is the first pilot study that demonstrates that PDL can be effective for the treatment of high-risk BCCs. Until further scientific evidence is available, treatment of high-risk BCCs should include histologic confirmation of clearance. Keywords Basal cell carcinoma . High-risk nonmelanoma skin cancer . Mohs micrographic surgery . Pulsed dye laser
Introduction Nonmelanoma skin cancers, mainly basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), are the most common malignancies in humans. Approximately 70 % of all skin cancers correspond to BCC [1]. Their biological behavior varies depending on the histologic subtype, the location, size, and the treatment used [2]. Many treatment alternatives have been reported with different clinical and histological outcomes. Surgical excision is the most commonly used treatment for BCC, and it is a technique that permits histological evaluation of the resection margins [3]. Mohs micrographic surgery (MMS) is the therapeutic alternative for BCC with the highest cure rates and also allows for the maximum tissue conservation. The most important risk factors for recurrence include morphoeic, infiltrative, micronodular, and basosquamous subtypes; location in the “H-zone” of the face; recurrent tumors; and poorly defined clinical borders or
Lasers Med Sci
immunosuppression. In the presence of such risk factors, treatment with MMS is recommended [4]. Several recent reports have described the use of pulsed dye laser (PDL) for the treatment of BCCs [5–7]. Although the exact mechanism of action of using PDL to treat BCCs is unclear, the main hypothesis is that PDL has an antiangiogenic effect [8]. BCCs have been shown to utilize a specialized tumor-associated microvasculature for growth [9]. In vitro studies have shown that increased expression of some chemokine receptors can enhance angiogenesis and carcinogenesis of BCC cells and that these receptors are expressed in more aggressive BCC subtypes [10]. In vivo imaging studies have confirmed that BCCs have abundant blood vessels demonstrating prominent tortuosity [11]. All these findings support that PDL could be used to selectively target the tumor’s vascular supply with the advantage of the preservation of surrounding normal tissue [12]. Most studies on PDL treatment of BCCs have focused on low-risk lesions. PDL seems to represent an effective and safe treatment for superficial and nodular BCCs located on the trunk and extremities, where complete clinical response can be expected in around 90 % of cases [9, 13]. Nevertheless, experience with PDL in the treatment of high-risk BCCs is limited. Incomplete responses and recurrences have been seen in aggressive histologic subtypes [8]. Another important limitation of previous studies in regard to assessing the real effectiveness of PDL in BCCs has been the lack of confirmation of the histologic clearance [7]. In some of the largest studies, many patients refused a skin biopsy or any surgical procedure after PDL due to the excellent clinical result without signs of persistent tumor or recurrence during the follow-up visits [8, 13]. The treatment of high-risk BCCs with PDL should include surgical excision to assess the histologic results of PDL treatment, especially in the facial area where MMS remains the gold standard. The aim of this study was to assess the effectiveness of PDL for the treatment of high-risk BCCs performing complete histologic evaluation of the treated area with MMS.
Cynosure, Inc., Westford, MA, USA). Laser therapy was performed using a spot size of 7 mm, a pulse duration of 2 ms, and a fluence of 15 J/cm2. There was a 10 % overlap of pulses, and the treatment included the BCC and a 4-mm margin of clinically normal skin. Two stacked pulses with a 1s delay between them were applied during each treatment session. Continuous airflow cooling at its maximum level “6” (Cryo5©, Zimmer MedizinSysteme GmbH, Neu-Ulm, Germany) was used. Post-laser care consisted of daily application of fusidic acid ointment (Fucidine©, LEO Pharma S.A., Barcelona, Spain) until any crusts had cleared. Standardized photographs and measurements of the lesion size were taken before treatment and 4 weeks after each laser treatment. The skin area was evaluated for adverse effects caused by the laser treatment immediately after the treatment and prior to the next session. Subsequently, MMS was performed at least 4 weeks after the final laser treatment. Surgical excision with MMS was performed with local anesthesia and sedation. The tumor margins according to the clinical photographs taken before PDL treatment were marked on the patient’s skin prior to excision in order to permit a complete histological evaluation despite the apparent clinical response. Thus, the removed tissue included apparently normal or scarred skin. The surgical process is described in Fig. 1. First, tumor debulking of the complete area where the tumor had been was performed using a scalpel for standard histologic evaluation in paraffinembedded tissue. These excisional tissue specimens were sectioned and processed according to routine practice, with complete examination of the specimen on hematoxylin and eosin (H&E) stains. The diagnostic biopsies performed prior to inclusion were also reviewed to assess the tumor depth and the BCCs histologic morphology. Finally, MMS using frozen fresh tissue sections of the defect after debulking plus a 4-mm margin were also examined. After confirmation of clear margins, the resulting defect was repaired. All tissue specimens were processed and analyzed at the Department of Pathology at the Ramón y Cajal University Hospital.
Materials and methods
Results
The Ethical Committee of Clinical Research at the Ramón y Cajal University Hospital gave approval for this study prior to patient recruitment. Seven patients with seven biopsy-proven high-risk BCCs located on the face (i.e., candidates for treatment with MMS) were recruited from the Department of Dermatology at the Ramón y Cajal Hospital (Madrid, Spain) from October 2012 to April 2013 and accepted inclusion in this study. All seven patients received three sessions of PDL at a wavelength of 595 nm with 4-week intervals (Cynergy®,
Seven patients with one high-risk BCC each were included in the study (two male and five female patients, age range from 50 to 90 years). All patients were Caucasian with Fitzpatrick skin types II–III. All lesions were located on the face, and the indications for MMS were infiltrative BCC, recurrent BCC, and/or nodular BCC >6 mm in diameter located in the H-zone. The clinical characteristics are detailed in Table 1. After each PDL treatment, immediate intense purpura or even whitening was evident in all cases, which we considered the desired clinical endpoint. All patients complained of
Lasers Med Sci
Fig. 1 a Tumor debulking specimen. b First stage of Mohs micrographic surgery. c Defect in healthy perilesional skin
moderate pain during treatment. Side effects included purpura that lasted 1 or 2 weeks after each PDL session (seven of Fig. 3 Nodular BCC measuring 20 mm (case 6). a Clinical photograph before treatment. b Clinical photograph after two PDL sessions. c Clinical photograph immediately before MMS and after three PDL sessions. d Clinical photograph after MMS showing the final surgical defect. e Final clinical result 11 months after surgery
Fig. 2 Infiltrative BCC measuring 6 mm (case 1). a Clinical photograph before PDL treatment. b Purpura immediately after PDL. c Clinical photograph after two PDL sessions. d Clinical photograph immediately before MMS after three PDL sessions with the surgical margins marked out. e Clinical photograph after the first and final stage of MMS
seven patients), erosions with crust formation that resolved in 2–3 weeks after each laser treatment (six of seven patients), and mild scarring or textural changes lasting 1–2 months after the last laser treatment that could therefore be noted immediately before surgery (4 of 7 patients). The clinical response was assessed before MMS. Complete clinical response was achieved in five of seven cases (71.4 %). In these cases, signs of residual tumor were not seen upon clinical and dermoscopic examination. Two patients (cases 5 and 7) showed residual tumor after PDL treatment, but significant reduction in size was achieved based on the comparison with clinical photographs. Case 5 showed a suspicious area of 6 mm (previous BCC measuring 18 mm), and case 7 showed a posttreatment maximum diameter of 9 mm (previous BCC measuring 14 mm). MMS was performed in six of the seven patients, 4–8 weeks after the last PDL session. One patient (case 3) with apparent complete clinical clearance after PDL refused to undergo MMS after suffering an anaphylactic shock in the operating room due to the premedication received. Fourteen months later, he
Lasers Med Sci Fig. 4 a Case 1. Punch biopsy specimen prior to PDL treatment showing an infiltrative BCC affecting deep reticular dermis. b Case 1. Representative histologic section from the tumor debulking specimen after PDL treatment without histologic evidence of BCC but significant dermal fibrosis. c Case 5. Diagnostic punch biopsy specimen demonstrating a nodular and infiltrative BCC extending to the superficial reticular dermis. d Case 5. Histologic section from the tumor debulking specimen after PDL treatment showing evidence of residual BCC
showed a clinical recurrence that was confirmed histologically. In the patients who underwent MMS, clear margins were achieved after a single stage in all six cases (100 %). The histologic evaluation of the tumor debulking specimens showed complete response in four cases (66.6 %), with no evidence of residual disease. In all the specimens, a variable degree of dermal fibrosis with horizontally oriented collagen bundles, mild vascular ectasia, and lymphohistiocytic inflammation was noted. None of the patients treated with
MMS have shown evidence of clinical recurrence after 10– 14 months of follow-up. The histologic examination of the previous diagnostic biopsies showed BCC affecting the deep reticular dermis in five of the six cases which underwent MMS. In patient 5, the diagnostic biopsy only showed involvement of the superficial reticular dermis, but 2 years had passed between the biopsy and inclusion in the study so it is possible that it had grown into deeper layers (Figs. 2, 3 and 4).
Lasers Med Sci Table 1 Clinical characteristics and histologic results after laser treatment Patient Age BCC type
Site
1
61
Infiltrative
2
84
3
65
Nodular, recurrent Nodular
Cheek 6 (paranasal) Eyebrow 9
4
79
5
90
6 7
50
Nodular, recurrent Nodularinfiltrative Nodular
Nasolabial fold Medial canthus Lateral nose Upper lip
85
Nodular
Ala nasi
Size PDL MMS Stages Clinical (mm) sessions of result after MMS PDL 3
Yes
1
3
Yes
1
10
3
No
–
7
3
Yes
1
18
3
Yes
1
20
3
Yes
1
14
3
Yes
1
Complete response Complete response Complete response Complete response Incomplete response Complete response Incomplete response
Histology Clinical at FU visits
FU PDL side (m) effects
Negative
14
Purpura
11
Purpura, crusts, scar Purpura, crusts Purpura, crusts, scar Purpura, crusts, scar Purpura, crusts, scar Purpura, crusts
Negative – Negative Positive Negative Positive
No evidence of recurrence No evidence of recurrence Recurrence No evidence of recurrence No evidence of recurrence No evidence of recurrence No evidence of recurrence
14 10 12 11 10
PDL pulsed dye laser, MMS Mohs micrographic surgery, FU follow-up
Discussion To our knowledge, this pilot study is the first to demonstrate with histologic confirmation that PDL can be effective for the treatment of some high-risk BCCs in the facial area. Several previous studies have described the effectiveness of PDL for BCCs but mainly in superficial or nodular BCCs located on the trunk or extremities [9, 13–15]. Minars et al. treated various BCC subtypes including facial lesions and even infiltrative BCCs. Despite using different numbers of sessions, they found worse response in such lesions [8]. The common limitation of these studies is the lack of histologic confirmation. The main reason for this has been the patient’s refusal of undergoing further surgical procedures or biopsies since they were content with the clinical and cosmetic results achieved with laser treatment [7, 8, 13]. Nevertheless, we must be cautious when treating high-risk BCCs, and confirmation of the histologic clearance should be mandatory. We chose MMS to ensure the safety of the patients as this technique obtains the highest cure rates and lowest recurrence rates [3]. The treatment parameters for PDL treatment of BCCs are currently not standardized. Most of the largest reports used several single-pass treatments with settings of 15 J/cm2, 3 ms, and a 7-mm spot size [8, 9, 13]. In a previous study that used PDL for nonmelanoma skin cancers (mainly BCCs), it was suggested that double-stacked pulsing could contribute to an increased destruction in a single treatment [15]. Based on the possibility of achieving a deeper penetration, combined PDL and Nd:YAG laser treatment may also be effective for lowrisk BCCs [12]. After considering these findings, and according to the high-risk nature of our patients’ BCCs, we decided to perform three treatments with similar PDL parameters as used in previous studies (i.e., a spot size of 7 mm, a pulse
duration of 2 ms, and a fluence of 15 J/cm2) but with two stacked pulses per session. The results of our study showed that PDL was unsuccessful in three cases, but complete histologic response was achieved in four of the six BCCs which were finally excised. Interestingly, these four BCCs included a tumor with an infiltrative subtype, two recurrent tumors, and one large tumor (>1.5 cm) in the H-zone. In some previous studies, large BCCs (>1.5 cm) showed a significantly worse response [9, 14]. As PDL does not penetrate more than 2 mm [13], treatment is expected to be unsuccessful in deeper tumors where vessels cannot be targeted. The use of two stacked pulses can increase the depth of penetration and the energy density generated [15]. Our findings are in agreement with this statement since we observed no residual disease in the tumor debulking specimens after PDL in four tumors that showed deep reticular involvement in the diagnostic biopsies. Although the real relationship between tumor size, tumor depth, and effectiveness of PDL remains elusive, the powerful parameters used in our study may explain the treatment outcome. Regarding adverse effects, it has to be noted that four of our patients showed mild scarring in the treatment area after three PDL sessions. Scarring was not reported as frequently in previous studies possibly due to the lower amount of laser energy delivered [8, 9, 13]. Most candidates for MMS have BCCs located in cosmetically important areas, so further studies are needed to refine the PDL parameters for the best cosmetic and oncologic results. In the two patients without complete clinical clearance after PDL, reduction in tumor size was still achieved. Reduced tumor size prior to surgical removal of a BCC could reduce the size of the defect and therefore also improve the cosmetic result. However, this approach may also lead to multifocal
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growth of the remaining BCC tissue and a higher risk of recurrence despite surgery. An important limitation in this study is the small cohort size. Therefore, definitive conclusions about PDL effectiveness in high-risk BCCs cannot be made. However, our results suggest that PDL could possibly become a future second-line therapeutic option for multiple subtypes of BCC.
Ethical standards The Ethical Committee of Clinical Research at the Ramón y Cajal University Hospital gave approval for this study prior to patient recruitment. All patients gave their informed consent prior to their inclusion in the study. Conflict of interest None declared. Funding sources None declared.
References 1. Le Boit PE, Burg G, Weedon D, Sarasin A (2006) Keratinocytic tumours. Pathology and genetics, skin tumours. World Health Organization classification of tumours. IARC Press, Lyon 2. McGuire JF, Ge NN, Dyson S (2009) Nonmelanoma skin cancer of the head and neck I: histopathology and clinical behavior. Am J Otolaryngol 30:121–33 3. Veronese F, Farinelli P, Zavattaro E, Zuccoli R, Bonvini D, Leigheb G, Colombo E (2012) Basal cell carcinoma of the head region: therapeutical results of 350 lesions treated with Mohs micrographic surgery. J Eur Acad Dermatol Venereol 26:838–43
4. Miller SJ (2000) The National Comprehensive Cancer Network (NCCN) guidelines of care for nonmelanoma skin cancers. Dermatol Surg 26:289–92 5. Allison KP, Kierman MN, Waters RA, Clement RM (2003) Pulsed dye laser teatment of superficial basal cell carcinoma: realistic or not? Lasers Med Sci 18:125–26 6. Campolmi P, Troiano M, Bonan P, Cannarozzo G, Lotti TM (2005) 595 nm pulsed dye laser for the treatment of superficial basal cell carcinoma. Lasers Med Sci 20:147–148 7. Campolmi P, Troiano M, Bonan P, Cannarozzo G, Lotti T (2008) Vascular based non conventional dye laser treatment for basal cell carcinoma. Dermatol Ther 21:402–405 8. Minars N, Blyumin-Karasik M (2012) Treatment of basal cell carcinomas with pulsed dye laser: a case series. J Skin Cancer 2012: 286480. doi:10.1155/2012/286480 9. Shah SM, Konnikov N, Duncan LM, Tannous ZS (2009) The effect of 595 nm pulsed dye laser on superficial and nodular basal cell carcinomas. Lasers Surg Med 41:417–422 10. Chen GS, Yu HS, Lan CC, Chow KC, Lin TY, Kok LF, Lu MP, Liu CH, Wu MT (2006) CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma. Br J Dermatol 154:910–8 11. González S, Tannous Z (2002) Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. J Am Acad Dermatol 47: 869–874 12. Jalian HR, Avram MM, Stankiewicz KJ, Shofner JD, Tannous Z (2014) Combined 585 nm pulsed-dye and 1,064 nm Nd:YAG lasers for the treatment of basal cell carcinoma. Lasers Surg Med 46:1–7 13. Konnikov N, Avram M, Jarell A, Tannous ZS (2011) Pulsed dye laser as a novel non-surgical treatment for basal cell carcinomas: response and follow up 12–21 months after treatment. Lasers Surg Med 43:72–78 14. Ballard CJ, Rivas MP, McLeod MP, Choudhary S, Elgart GW, Nouri K (2011) The pulsed dye laser for the treatment of basal cell carcinoma. Lasers Med Sci 26:641–644 15. Tran HT, Lee RA, Oganesyan G, Jiang SB (2012) Single treatment of non-melanoma skin cancers using a pulsed-dye laser with stacked pulses. Lasers Surg Med 44(6):459–67
BRIEF REPORT
The effect of pulsed dye laser on high-risk basal cell carcinomas with response control by Mohs micrographic surgery Leticia Alonso-Castro & Luis Ríos-Buceta & Pablo Boixeda & John Paoli & Carmen Moreno & Pedro Jaén
Received: 6 May 2014 / Accepted: 23 October 2014 # Springer-Verlag London 2014
Abstract Several reports have shown the effectiveness of pulsed dye laser (PDL) for the treatment of basal cell carcinoma (BCC). Most studies have focused on low-risk BCCs, but an important limitation has been the lack of histologic confirmation of the treatment results. The aim of this study was to assess the effectiveness of PDL in high-risk BCCs with complete histologic evaluation with Mohs micrographic surgery (MMS). Seven patients with high-risk BCCs located on the face were included. All tumors were treated with three sessions of PDL (595 nm) at 4-week intervals. The tumor and 4 mm of peripheral skin were treated with two stacked pulses with a 1-s delay, a fluence of 15 J/cm2, a pulse duration of 2 ms, and a spot size of 7 mm. MMS was performed at least 1 month after the last PDL session including excisional tumor L. Alonso-Castro (*) : L. Ríos-Buceta : P. Boixeda : J. Paoli : P. Jaén Department of Dermatology, Ramón y Cajal University Hospital, Madrid, Spain e-mail: [email protected] L. Ríos-Buceta e-mail: [email protected] P. Boixeda e-mail: [email protected] J. Paoli e-mail: [email protected] P. Jaén e-mail: [email protected] J. Paoli Department of Dermatology, Sahlgrenska University Hospital, Institute of Clinical Sciences at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden C. Moreno Department of Pathology, Ramón y Cajal University Hospital, Madrid, Spain e-mail: [email protected]
debulking prior to the first stage of MMS for standard histologic evaluation. Apparent complete clinical response was achieved in five of seven patients. MMS was finally performed in six patients, and clear margins were achieved after one stage of MMS. The histologic evaluation of the tumor debulking specimens showed complete clearance in four of six cases. One patient who did not undergo MMS showed a recurrence after 14 months. This is the first pilot study that demonstrates that PDL can be effective for the treatment of high-risk BCCs. Until further scientific evidence is available, treatment of high-risk BCCs should include histologic confirmation of clearance. Keywords Basal cell carcinoma . High-risk nonmelanoma skin cancer . Mohs micrographic surgery . Pulsed dye laser
Introduction Nonmelanoma skin cancers, mainly basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), are the most common malignancies in humans. Approximately 70 % of all skin cancers correspond to BCC [1]. Their biological behavior varies depending on the histologic subtype, the location, size, and the treatment used [2]. Many treatment alternatives have been reported with different clinical and histological outcomes. Surgical excision is the most commonly used treatment for BCC, and it is a technique that permits histological evaluation of the resection margins [3]. Mohs micrographic surgery (MMS) is the therapeutic alternative for BCC with the highest cure rates and also allows for the maximum tissue conservation. The most important risk factors for recurrence include morphoeic, infiltrative, micronodular, and basosquamous subtypes; location in the “H-zone” of the face; recurrent tumors; and poorly defined clinical borders or
Lasers Med Sci
immunosuppression. In the presence of such risk factors, treatment with MMS is recommended [4]. Several recent reports have described the use of pulsed dye laser (PDL) for the treatment of BCCs [5–7]. Although the exact mechanism of action of using PDL to treat BCCs is unclear, the main hypothesis is that PDL has an antiangiogenic effect [8]. BCCs have been shown to utilize a specialized tumor-associated microvasculature for growth [9]. In vitro studies have shown that increased expression of some chemokine receptors can enhance angiogenesis and carcinogenesis of BCC cells and that these receptors are expressed in more aggressive BCC subtypes [10]. In vivo imaging studies have confirmed that BCCs have abundant blood vessels demonstrating prominent tortuosity [11]. All these findings support that PDL could be used to selectively target the tumor’s vascular supply with the advantage of the preservation of surrounding normal tissue [12]. Most studies on PDL treatment of BCCs have focused on low-risk lesions. PDL seems to represent an effective and safe treatment for superficial and nodular BCCs located on the trunk and extremities, where complete clinical response can be expected in around 90 % of cases [9, 13]. Nevertheless, experience with PDL in the treatment of high-risk BCCs is limited. Incomplete responses and recurrences have been seen in aggressive histologic subtypes [8]. Another important limitation of previous studies in regard to assessing the real effectiveness of PDL in BCCs has been the lack of confirmation of the histologic clearance [7]. In some of the largest studies, many patients refused a skin biopsy or any surgical procedure after PDL due to the excellent clinical result without signs of persistent tumor or recurrence during the follow-up visits [8, 13]. The treatment of high-risk BCCs with PDL should include surgical excision to assess the histologic results of PDL treatment, especially in the facial area where MMS remains the gold standard. The aim of this study was to assess the effectiveness of PDL for the treatment of high-risk BCCs performing complete histologic evaluation of the treated area with MMS.
Cynosure, Inc., Westford, MA, USA). Laser therapy was performed using a spot size of 7 mm, a pulse duration of 2 ms, and a fluence of 15 J/cm2. There was a 10 % overlap of pulses, and the treatment included the BCC and a 4-mm margin of clinically normal skin. Two stacked pulses with a 1s delay between them were applied during each treatment session. Continuous airflow cooling at its maximum level “6” (Cryo5©, Zimmer MedizinSysteme GmbH, Neu-Ulm, Germany) was used. Post-laser care consisted of daily application of fusidic acid ointment (Fucidine©, LEO Pharma S.A., Barcelona, Spain) until any crusts had cleared. Standardized photographs and measurements of the lesion size were taken before treatment and 4 weeks after each laser treatment. The skin area was evaluated for adverse effects caused by the laser treatment immediately after the treatment and prior to the next session. Subsequently, MMS was performed at least 4 weeks after the final laser treatment. Surgical excision with MMS was performed with local anesthesia and sedation. The tumor margins according to the clinical photographs taken before PDL treatment were marked on the patient’s skin prior to excision in order to permit a complete histological evaluation despite the apparent clinical response. Thus, the removed tissue included apparently normal or scarred skin. The surgical process is described in Fig. 1. First, tumor debulking of the complete area where the tumor had been was performed using a scalpel for standard histologic evaluation in paraffinembedded tissue. These excisional tissue specimens were sectioned and processed according to routine practice, with complete examination of the specimen on hematoxylin and eosin (H&E) stains. The diagnostic biopsies performed prior to inclusion were also reviewed to assess the tumor depth and the BCCs histologic morphology. Finally, MMS using frozen fresh tissue sections of the defect after debulking plus a 4-mm margin were also examined. After confirmation of clear margins, the resulting defect was repaired. All tissue specimens were processed and analyzed at the Department of Pathology at the Ramón y Cajal University Hospital.
Materials and methods
Results
The Ethical Committee of Clinical Research at the Ramón y Cajal University Hospital gave approval for this study prior to patient recruitment. Seven patients with seven biopsy-proven high-risk BCCs located on the face (i.e., candidates for treatment with MMS) were recruited from the Department of Dermatology at the Ramón y Cajal Hospital (Madrid, Spain) from October 2012 to April 2013 and accepted inclusion in this study. All seven patients received three sessions of PDL at a wavelength of 595 nm with 4-week intervals (Cynergy®,
Seven patients with one high-risk BCC each were included in the study (two male and five female patients, age range from 50 to 90 years). All patients were Caucasian with Fitzpatrick skin types II–III. All lesions were located on the face, and the indications for MMS were infiltrative BCC, recurrent BCC, and/or nodular BCC >6 mm in diameter located in the H-zone. The clinical characteristics are detailed in Table 1. After each PDL treatment, immediate intense purpura or even whitening was evident in all cases, which we considered the desired clinical endpoint. All patients complained of
Lasers Med Sci
Fig. 1 a Tumor debulking specimen. b First stage of Mohs micrographic surgery. c Defect in healthy perilesional skin
moderate pain during treatment. Side effects included purpura that lasted 1 or 2 weeks after each PDL session (seven of Fig. 3 Nodular BCC measuring 20 mm (case 6). a Clinical photograph before treatment. b Clinical photograph after two PDL sessions. c Clinical photograph immediately before MMS and after three PDL sessions. d Clinical photograph after MMS showing the final surgical defect. e Final clinical result 11 months after surgery
Fig. 2 Infiltrative BCC measuring 6 mm (case 1). a Clinical photograph before PDL treatment. b Purpura immediately after PDL. c Clinical photograph after two PDL sessions. d Clinical photograph immediately before MMS after three PDL sessions with the surgical margins marked out. e Clinical photograph after the first and final stage of MMS
seven patients), erosions with crust formation that resolved in 2–3 weeks after each laser treatment (six of seven patients), and mild scarring or textural changes lasting 1–2 months after the last laser treatment that could therefore be noted immediately before surgery (4 of 7 patients). The clinical response was assessed before MMS. Complete clinical response was achieved in five of seven cases (71.4 %). In these cases, signs of residual tumor were not seen upon clinical and dermoscopic examination. Two patients (cases 5 and 7) showed residual tumor after PDL treatment, but significant reduction in size was achieved based on the comparison with clinical photographs. Case 5 showed a suspicious area of 6 mm (previous BCC measuring 18 mm), and case 7 showed a posttreatment maximum diameter of 9 mm (previous BCC measuring 14 mm). MMS was performed in six of the seven patients, 4–8 weeks after the last PDL session. One patient (case 3) with apparent complete clinical clearance after PDL refused to undergo MMS after suffering an anaphylactic shock in the operating room due to the premedication received. Fourteen months later, he
Lasers Med Sci Fig. 4 a Case 1. Punch biopsy specimen prior to PDL treatment showing an infiltrative BCC affecting deep reticular dermis. b Case 1. Representative histologic section from the tumor debulking specimen after PDL treatment without histologic evidence of BCC but significant dermal fibrosis. c Case 5. Diagnostic punch biopsy specimen demonstrating a nodular and infiltrative BCC extending to the superficial reticular dermis. d Case 5. Histologic section from the tumor debulking specimen after PDL treatment showing evidence of residual BCC
showed a clinical recurrence that was confirmed histologically. In the patients who underwent MMS, clear margins were achieved after a single stage in all six cases (100 %). The histologic evaluation of the tumor debulking specimens showed complete response in four cases (66.6 %), with no evidence of residual disease. In all the specimens, a variable degree of dermal fibrosis with horizontally oriented collagen bundles, mild vascular ectasia, and lymphohistiocytic inflammation was noted. None of the patients treated with
MMS have shown evidence of clinical recurrence after 10– 14 months of follow-up. The histologic examination of the previous diagnostic biopsies showed BCC affecting the deep reticular dermis in five of the six cases which underwent MMS. In patient 5, the diagnostic biopsy only showed involvement of the superficial reticular dermis, but 2 years had passed between the biopsy and inclusion in the study so it is possible that it had grown into deeper layers (Figs. 2, 3 and 4).
Lasers Med Sci Table 1 Clinical characteristics and histologic results after laser treatment Patient Age BCC type
Site
1
61
Infiltrative
2
84
3
65
Nodular, recurrent Nodular
Cheek 6 (paranasal) Eyebrow 9
4
79
5
90
6 7
50
Nodular, recurrent Nodularinfiltrative Nodular
Nasolabial fold Medial canthus Lateral nose Upper lip
85
Nodular
Ala nasi
Size PDL MMS Stages Clinical (mm) sessions of result after MMS PDL 3
Yes
1
3
Yes
1
10
3
No
–
7
3
Yes
1
18
3
Yes
1
20
3
Yes
1
14
3
Yes
1
Complete response Complete response Complete response Complete response Incomplete response Complete response Incomplete response
Histology Clinical at FU visits
FU PDL side (m) effects
Negative
14
Purpura
11
Purpura, crusts, scar Purpura, crusts Purpura, crusts, scar Purpura, crusts, scar Purpura, crusts, scar Purpura, crusts
Negative – Negative Positive Negative Positive
No evidence of recurrence No evidence of recurrence Recurrence No evidence of recurrence No evidence of recurrence No evidence of recurrence No evidence of recurrence
14 10 12 11 10
PDL pulsed dye laser, MMS Mohs micrographic surgery, FU follow-up
Discussion To our knowledge, this pilot study is the first to demonstrate with histologic confirmation that PDL can be effective for the treatment of some high-risk BCCs in the facial area. Several previous studies have described the effectiveness of PDL for BCCs but mainly in superficial or nodular BCCs located on the trunk or extremities [9, 13–15]. Minars et al. treated various BCC subtypes including facial lesions and even infiltrative BCCs. Despite using different numbers of sessions, they found worse response in such lesions [8]. The common limitation of these studies is the lack of histologic confirmation. The main reason for this has been the patient’s refusal of undergoing further surgical procedures or biopsies since they were content with the clinical and cosmetic results achieved with laser treatment [7, 8, 13]. Nevertheless, we must be cautious when treating high-risk BCCs, and confirmation of the histologic clearance should be mandatory. We chose MMS to ensure the safety of the patients as this technique obtains the highest cure rates and lowest recurrence rates [3]. The treatment parameters for PDL treatment of BCCs are currently not standardized. Most of the largest reports used several single-pass treatments with settings of 15 J/cm2, 3 ms, and a 7-mm spot size [8, 9, 13]. In a previous study that used PDL for nonmelanoma skin cancers (mainly BCCs), it was suggested that double-stacked pulsing could contribute to an increased destruction in a single treatment [15]. Based on the possibility of achieving a deeper penetration, combined PDL and Nd:YAG laser treatment may also be effective for lowrisk BCCs [12]. After considering these findings, and according to the high-risk nature of our patients’ BCCs, we decided to perform three treatments with similar PDL parameters as used in previous studies (i.e., a spot size of 7 mm, a pulse
duration of 2 ms, and a fluence of 15 J/cm2) but with two stacked pulses per session. The results of our study showed that PDL was unsuccessful in three cases, but complete histologic response was achieved in four of the six BCCs which were finally excised. Interestingly, these four BCCs included a tumor with an infiltrative subtype, two recurrent tumors, and one large tumor (>1.5 cm) in the H-zone. In some previous studies, large BCCs (>1.5 cm) showed a significantly worse response [9, 14]. As PDL does not penetrate more than 2 mm [13], treatment is expected to be unsuccessful in deeper tumors where vessels cannot be targeted. The use of two stacked pulses can increase the depth of penetration and the energy density generated [15]. Our findings are in agreement with this statement since we observed no residual disease in the tumor debulking specimens after PDL in four tumors that showed deep reticular involvement in the diagnostic biopsies. Although the real relationship between tumor size, tumor depth, and effectiveness of PDL remains elusive, the powerful parameters used in our study may explain the treatment outcome. Regarding adverse effects, it has to be noted that four of our patients showed mild scarring in the treatment area after three PDL sessions. Scarring was not reported as frequently in previous studies possibly due to the lower amount of laser energy delivered [8, 9, 13]. Most candidates for MMS have BCCs located in cosmetically important areas, so further studies are needed to refine the PDL parameters for the best cosmetic and oncologic results. In the two patients without complete clinical clearance after PDL, reduction in tumor size was still achieved. Reduced tumor size prior to surgical removal of a BCC could reduce the size of the defect and therefore also improve the cosmetic result. However, this approach may also lead to multifocal
Lasers Med Sci
growth of the remaining BCC tissue and a higher risk of recurrence despite surgery. An important limitation in this study is the small cohort size. Therefore, definitive conclusions about PDL effectiveness in high-risk BCCs cannot be made. However, our results suggest that PDL could possibly become a future second-line therapeutic option for multiple subtypes of BCC.
Ethical standards The Ethical Committee of Clinical Research at the Ramón y Cajal University Hospital gave approval for this study prior to patient recruitment. All patients gave their informed consent prior to their inclusion in the study. Conflict of interest None declared. Funding sources None declared.
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