Photodermatology, Photoimmunology & Photomedicine
ORIGINAL ARTICLE
Usefulness of in vivo photodiagnosis for the identification of tumor margins in recurrent basal cell carcinoma of the face Riccardo G. Borroni1, Stefania Barruscotti2, Andrea Carugno2, Vincenzo Barbaccia2, Eloisa Arbustini1 & Valeria Brazzelli2
1 Laboratori Sperimentali di Ricerca – Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 2 Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Key words: basal cell carcinoma; fluorescence diagnosis; methylaminolevulinate; photodiagnosis
Correspondence: Valeria Brazzelli, M.D., Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, 27100, Pavia, Italy. Tel: +39 0382 503794 Fax: +39 0382 526379 e-mails: [email protected]; [email protected]
Accepted for publication: 28 January 2015
Funding sources:
SUMMARY Background Basal cell carcinoma (BCC) is the most frequent malignant tumor of the skin. The high prevalence of BCC, the risk of local recurrence, and the difficult clinical identification of the excision margins emphasize the importance of studying new approaches, ensuring complete surgical excision that allows preservation of normal tissue, especially for BCCs located on cosmetically important areas such as the mid face. Photodiagnosis (PD) is a preoperative technique that allows a more accurate distinction of neoplastic lesions from surrounding healthy skin in vivo. Purpose The aim of this study is to assess the usefulness of PD for the evaluation of tumor margins in 10 patients with recurrent BCC of the face. Methods We study the red fluorescence emitted by neoplastic tissue under a Wood’s lamp irradiation, after accumulation of methyl amino levulinate (MAL) cream in 10 patients with recurrent BCC. Results Our histologic analysis of perilesional skin by PD allowed to delineate more precise tumor margins, thus achieving radical excision in 90% of patients. Conclusion PD represents a diagnostic method that helps to distinguish between tumor tissue and surrounding healthy tissue especially in case of recurrent BCC of the face when the clinical delimitation is not clear.
RGB is recipient of the scholarship no. 604 by Fondazione IRCCS ‘San Matteo’, Pavia, titled ‘Terapia fotodinamica topica di precancerosi e carcinomi cutanei in pazienti trapiantati’.
Conflicts of interest: None declared.
Photodermatol Photoimmunol Photomed 2015; 31: 195–201
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12166
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Basal cell carcinoma (BCC) is the most frequent malignant tumor of the skin, and it accounts for 80% of nonmelanoma skin cancer. The incidence is more than 2 million new cases each year worldwide (1). Clinical diagnosis of BCC is straightforward in most cases, and the diagnostic accuracy can be increased by dermoscopy (2). When clinical diagnosis is not certain or when the histologic subtype of BCC may influence the therapeutic approach and the patient’s prognosis, skin biopsy with histologic examination may be required (3). Surgical removal with histologic control of excision margins usually represents the first choice in the treatment of BCC and is the most widely used option with the best outcome (4). Despite careful evaluation of tumor margins, incomplete excision of BCC is common. The recurrence rate after surgical excision of BCC at 5 years is calculated between 4.1% and 10.1% (5). For completely excised lesions with tumor-free resection margins, the 5-year recurrence rate is less than 2% (6) but significantly increases up to 41% in case of incomplete surgical excision (7). The impact of local recurrence is particularly relevant in BCC of the face, especially when lesions are located on the nose, perioral and periauricular regions. Boulinguez et al. showed that 24% of incompletely excised BCCs present with increased aggressive course on recurrence, especially if located in the nasal and periauricular regions (8). Furthermore, the recurrence of BCC after incomplete surgical excision or less effective nonsurgical options may lead to the formation of areas of scar tissue in which recurring BCC may be difficult to distinguish from surrounding healthy skin (4). The high prevalence of BCC, the risk of local recurrence, and the difficult clinical identification of tumor margins emphasize the importance of studying new diagnostic and therapeutic techniques, including exact demarcation of tumor margins ensuring complete surgical excision with preservation of normal tissue, especially for BCCs located on cosmetically important areas such as the mid face. The possibility of using fluorescence for the diagnosis of nonmelanoma skin cancer has been shown in a study conducted in 1998 by Svanberg et al. (9) and also more recently by Stenquist et al. (10) in 2005 and by Tierney et al. (11) in 2011, who have demonstrated the usefulness of in vivo fluorescence imaging in assisting the diagnosis, the treatment, and the follow-up of cutaneous neoplastic lesions. Photodiagnosis (PD), also referred to as fluorescence diagnosis, is a preoperative diagnostic method that
allows a more accurate demarcation of neoplastic lesions in vivo (12). Most commonly used techniques employ precursors of protoporphyrin IX (PpIX), namely d-5aminolaevulinic acid (ALA) and its methyl ester, methyl amino levulinate (MAL), as photosensitizers (13). These are topically applied on the lesional area and are converted into PpIX through the heme biosynthetic pathway (14). The increased activity of the enzyme PBG deaminase and the limited activity of the enzyme ferrochelatase in proliferating tumor cells explain the relatively higher accumulation of PpIX in neoplastic tissue as compared to normal epidermis (15). PpIX is a fluorescent compound with maximum absorption peak around 410 nm (blue) and emission in the spectrum of visible red light (16). Excitation of MAL-treated skin with appropriate wavelengths produces a red fluorescence corresponding to the tumor area, allowing identification of subclinical extent of the tumor. The aim of this study was to assess the usefulness of PD for the evaluation of tumor margins in 10 patients with recurrent BCC of the face, in which the clinical demarcation of tumor margins was difficult and not clear.
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Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PATIENTS AND METHODS Ten patients (four male and six female) presenting a clinical and histologic diagnosis of recurrent BCC of the face were included in this study. The age of the patients ranged from 44 to 78 (mean 70.4). Nine patients had a recurrence of BCC in the scar of the previous surgical excision, and one patient had a recurrence of BCC that had been previously treated with cryotherapy. Seven of the BCCs occurred on the nose, two on the forehead, and one on the scalp. According to histology of primary BCC excision, patients were affected by recurrence of six morpheiform subtype of BCC (60%), three superficial BCC (30%), and one pigmented BCC (10%). Clinical data were recorded for each patient, including relevant medical history with particular interest to comorbidities, concomitant medications, age, gender, anatomic site of skin lesions, and size of the lesional area. Clinically visible margins of each skin lesion were drawn with a dermographic pen, and the surface of each skin area was measured. Methyl-aminolevulinate (MAL) 160 mg/g cream (Metvix, Galderma Italia, Milano, Italy) was applied in a 1-mm thick layer, extending the application to clinically uninvolved skin in a range of 10 mm around the lesion. The area involved was then covered with a photo-opaque dressing to prevent the exposure to light
Photodiagnosis in recurrent BCCs of the face
and sealed for 3 h. After 3 h, the MAL film was removed, the excess cream was gently wiped off, and the lesion was irradiated using a Wood’s lamp (Philips TL8W/08) in a dark room. The margins of the lesional area emitting an intense red fluorescence were then drawn with a dermographic pen to obtain a clear demarcation between the tumor and the surrounding healthy skin, which was characterized by a dim red fluorescence (‘gray zone’). The margins were also reported on graph paper to calculate the lesional area and to apply it onto the surgical site pre-operatively. Clinical and fluorescence pictures were taken, respectively, before and during PD with a digital camera, positioned on a tripod at a distance of 40 cm from the skin. The surface of the fluorescent red area was measured and compared with the surface of the clinical area. To support the hypothesis of the absence of BCC in the dim fluorescent area, 4-mm punch skin biopsies for histopathological evaluation were taken in this ‘gray zone’ for each patient (Figs 1 and 2). In case of BBC negative in biopsies performed in the gray area, the margins of surgical excision corresponded to the margins of the red area. In case of positive result of histologic biopsies performed in the gray area, the surgical margins have been expanded extending beyond the BCC-positive site of biopsy.
According to the result of the data obtained with the red fluorescence imaging of the tumor area and the histologic result of skin biopsies outside the red area, surgical margins were drawn and a surgical excision of BCC subsequently was planned within a week. All patients gave written informed consent for participating to the study, which was conducted in accordance with the Declaration of Helsinki principles and was approved by the Ethics Committee of the Fondazione IRCCS Policlinico San Matteo of Pavia, Italy.
RESULTS Ten patients with ‘problematic’ BCC because of the number of recurrence, the location on the face, and the difficulties in defining the tumor margins were included in the study. In seven patients (70%), the BCC occurred on the nose, in two (20%) on the forehead, and in one (10%) on the scalp. Tumor area delimited by clinically visible margins ranged between 1.5 and 10 cm2 (mean area 3.68 3.29 cm2, Table 1). The tumor area evaluated by measurement of the bright red fluorescence evident with PD ranged from 1.73 cm2 to 14.75 cm2 (mean area 4.67 4.08 cm2, Table 1). A total of 29 biopsies in the ‘gray zone’ were performed (average of 2.9 biopsies for each patient),
(a)
(b)
(c)
(d)
Fig. 1. Patient 2, recurrence of BCC on left nasal ala after repeated cryotherapy sessions, (a) clinical presentation of the lesion on recurrence; (b) affected area illuminated with Wood lamp during PD; red arrow and gray arrow indicate ‘red’ zone and ‘gray’ zone, respectively; (c) Drawing of margins of the affected area after PD with biopsies site (small circles outside the ‘red area’); (d) drawing on graph paper of the clinically visible lesion (dotted line) of ‘red’ area (solid line) and ‘gray’ area (dashed line). Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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(a)
(b)
(c)
(d)
Fig. 2. Patient 4, recurrence of BCC on right nasal tip, (a) clinical aspect of the lesion at presentation; the dotted line indicates the area where MAL cream will be applied; (b) affected area illuminated with Wood lamp during PD; ‘red’ zone (red arrow) and ‘gray’ zone (gray arrow) are evident; (c) the drawing of margins of the affected area with biopsies site; (d) drawing on graph paper of the clinically definable lesion (dotted line) of ‘red’ area (solid line) and ‘gray’ area (dashed line).
depending on the size of the measured area, its location, and the more or less clear demarcation of the bright red area. Biopsies performed in the less fluorescent area confirmed the absence of neoplastic cells out of the red area in eight patients: 25 of 29 biopsies (86.2%) were free from BCC. Biopsies performed in the less fluorescent area were infiltrated by BCC in two patients (three biopsies in one patient and one biopsy in the other showed the presence of tumor cells): four of 29 biopsies (17.8%) were infiltrated by BCC (Table 1). Areas of surgical excision were obtained by integrating the results of the PD and histology and corresponded to the red area determined with PD in eight of 10 patients (80%), and in the remaining two patients (20%), the area has been enlarged compared to the red fluorescence, beyond BCC-positive site of biopsies. Surgical excision of all 10 BCC was then performed: for one patient (10%), the histologic evaluation of the area excised showed involvement of BCC in a resection margin, while in the other nine patients (90%), the surgical margins were not involved and BCC was completely excised.
DISCUSSION Complete excision of BCC should always be the goal of surgical treatment; however, incomplete excision of BCC 198
is frequent. Reported rates of incomplete excision after routine excision range from 1.9% to 16% (4). Recently, Walker and Hill reviewed 5-year follow-up studies and found an average of 38% recurrence rate (range 19– 100%) after incomplete BCC excision (6). Milroy and colleagues suggested that the aggressive behavior of BCCs may follow inadequate excision due to diagnostic uncertainty and cosmetic concerns (17). Factors contributing to incomplete excision include difficult to identify tumor margins, especially when prior surgical and nonsurgical treatments have altered tissue architecture, particularly evident after re-excision of flap repairs causing distortion of tissue planes and loss of tissue reservoirs used for the initial flap, often resulting in a large defects with limited repair options (4). Mohs micrographic surgery (MMS) has been shown to the most effective modality for removing high-risk BCCs located on the mid face and the ears. MMS has been demonstrated to have superior initial, 5-year recurrence rates, and cosmetic outcomes as compared to other treatment modalities, however, is expensive and requires long processing time. In the last years, in vivo reflectance confocal microscopy (RCM) has proven to be useful, noninvasive in vivo technique for real-time imaging of the epidermis and superficial dermis. RCM has been reported to be useful in the in vivo evaluation of skin tumors such as Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
M, 44
F, 67
F, 79
M, 74
F, 75
M, 69
F, 78
F, 75
M, 72
2
3
4
5
6
7
8
9
10
Nasal dorsum
Left nasal pyramid
Right temple
Scalp
Left ala
Nasal dorsum
Right nasal tip
Nasal dorsum
Left ala
Right forehead
Anatomic Site
Pigmented BCC recurrence
Morpheiform BCC recurrence
Superficial BCC recurrence
Morpheiform ulcerated BCC recurrence Morpheiform BCC recurrence
Morpheiform BCC recurrence
Morpheiform BCC recurrence
Superficial BCC recurrence
Morpheiform ulcerated BCC recurrence Superficial BCC recurrence
Diagnosis
29
2
2
3
4
25 free, 4 infiltrated
2 free
1 free 1 infiltrated
3 free
4 free
3 free
3 free
3
3
2 free
3 free
3 free
3 infiltrated 1 free
Histologic result of biopsies
2
3
3
4
N° biopsies
BCC, basal cell carcinoma; F, female; M, male; and PD, photodiagnosis.
70.4 10.0
F, 71
1
Patient (sex, age) Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Superficial BCC present in occasional microfoci of a resection margin Completely excised BCC with free resection margins Completely excised BCC with free resection margins 9 Completely excised BCC, 1 BCC present in a resection margin
Surgical excision of BCC
Table 1. Demographic and clinic-pathological features of patients, with recurrent BCC of the face
3.50
3.00
1.75
1.50
8.75
2.50
3.70
4.45 4.67 4.08
2.00
2.80
4.00 3.68 3.29
2.25
2.00
10.00
2.00
1.75
1.75
14.75
9.50
1.50
Size of PD area, (mm2)
Size of the clinical evident BCC area, (mm2)
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melanoma, squamous cell carcinoma, and BCC (18). The main limiting factors of this technique are • The limited depth of RCM penetration. • The requirement that the surface of the lesion margins is flat enough for examination. and • The presence of hyperkeratosis, thickness, or the anatomic site of lesions may make examination difficult or misleading. RCM can still be time consuming, and it requires well-trained medical staff, and, currently, the RCM device is particularly expensive (19). Alternative options to MMS or RCM may be necessary in settings where these techniques are not available and to have a good quality of surgical excision with cost-efficiency of the treatments. PD is a simple, noninvasive pre-operative investigation that allows a more accurate demarcation of neoplastic lesions and can help in increasing the efficiency of surgical excision. PD can be decisive in difficult cases of recurrent BCC, especially when the presence of scar tissue makes it difficult for the delimitation or when tumors are located in difficult sites, such as the face (12). In our study, we used PD to delineate tumor margins of clinically poorly defined, recurrent BCC of the face. By performing multiple punch skin biopsies in the dim fluorescent area surrounding the site of higher fluorescence, we demonstrate that PD can help the clinician to better define tumor margins. Biopsies performed in the area surrounding the site of higher fluorescence showed the absence of neoplastic cells in 86.2% of cases. In 17.8% of biopsies performed on the less fluorescent areas, however, biopsies showed recurrence of BCC. This could be explained by scar from previous incomplete
surgical excisions that could have hampered tissue penetration of MAL. Despite positivity of some skin biopsies performed in the ‘gray zone’, this result has allowed the surgeon to draw with good security the tumor margins and achieve radical excision in 90% of cases. The red fluorescent image obtained with PD, along with the histologic results of the biopsies in the less fluorescent area, allowed to remove all the BCC with a secure demarcation of tumor margins and gave information about the enlargement of the margins displayed with the PD. Our histologic analysis of perilesional skin by PD, allowed to delineate more precise tumor margins, thus achieving radical excision in the majority of patients. Although thise is a method that takes time, effort, and accuracy, it has allowed us to get a good result, with regard to the radicality. In the future, we plan to perform larger studies without histologic examination to reduce potential harm to cosmetically important areas of the face and limit procedure costs. In conclusion, in our cases, both PD and biopsy results together have represented a diagnostic method to obtain a clear distinction between the tumor tissue and the surrounding healthy tissue that were not possible with the only clinical diagnosis. In case of difficult BCCs, especially when recurrent or in difficult sites, where the presence of scar tissue makes it difficult to delimitate, and also the RCM would give unreliable results, PD with biopsies can increase up to 90% the percentage of completed excision of this type of tumors. In addition, our work, defining an area of intense red fluorescence that corresponds to the tumor area, suggests a future possibility of PD examination to guide the definitions of margins in primary BCC.
REFERENCES 1. Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 2002; 146(Suppl): 1–6. 2. Felder S, Rabinovitz H, Oliviero M, Kopf A. Dermoscopic differentiation of a superficial basal cell carcinoma and squamous cell carcinoma in situ. Dermatol Surg 2006; 32: 423– 425. 3. Costantino D, Lowe L, Brown DL. Basosquamous carcinoma – an underrecognized, high-risk cutaneous neoplasm: case study and review of the literature. J Plast Reconstr Aesthet Surg 2006; 59: 424–428. 4. Palmer VM, Wilson PR. Incompletely excised basal cell carcinoma: residual 200
tumor rates at Mohs re-excision. Dermatol Surg 2013; 39: 706–718. 5. Rowe DE, Carroll RJ, Day CL Jr. Longterm recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989; 15: 315–328. 6. Walker P, Hill D. Surgical treatment of basal cell carcinomas using standard postoperative histological assessment. Australas J Dermatol 2006; 47: 1–12. 7. Wilson AW, Howsam G, Santhanam V et al. Surgical management of incompletely excised basal cell carcinomas of the head and neck. Br J Oral Maxillofac Surg 2004; 42: 311–314.
8. Boulinguez S, Grison-Tabone C, Lamant L et al. Histological evolution of recurrent basal cell carcinoma and therapeutic implications for incompletely excised lesions. Br J Dermatol 2004; 151: 623–626. 9. Svanberg K, Wang I, Colleen S et al. Clinical multi-colour fluorescence imaging of malignant tumours–initial experience. Acta Radiol 1998; 39: 2–9. 10. Stenquist B, Ericson MB, Strandeberg C et al. Bispectral fluorescence imaging of aggressive basal cell carcinoma combined with histopathological mapping: a preliminary study indicating a possible adjunct to Mohs micrographic surgery. Br J Dermatol 2006; 154: 305–309.
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11. Tiereney E, Petersen J, Hancke W. Photodynamic diagnosis of tumor margins using methyl aminolevulimate before Mohs micrographic surgery. J Am Acad Dermatol 2011; 64: 911–918. 12. Allison RR, Sibata CH. Photodiagnosis for cutaneous malignancy: a brief clinical and technical review. Photodiagnosis Photodyn Ther 2008; 5: 247–250. 13. Pottier RH, Chow YF, LaPlante JP, Truscott TG, Kennedy JC, Beiner LA. Non invasive technique for obtaining fluorescence exitation and emission spectra in vivo. Photochem Photobiol 1986; 44: 679–687.
14. Kennedy JC, Pottier RH, Pross DC. PDT with endogenous protoporphyrin IX- basic principles and present clinical experience. J Photochem Photobiol, B 1990; 6: 143–148. 15. Dougherty TJ, Gomer CJ, Henderson BW et al. Photodynamic therapy. J Natl Cancer Inst 1998; 90: 889–905. 16. Vereecken P, Da Costa CM, Steels E, De Lathouwer O, Heenen M, De Mey A. Fluorescence diagnosis of face-located basal cell carcinomas: a new dermatological procedure which may help the surgeon. Acta Chir Belg 2007; 107: 205–207. 17. Milroy CJ, Horlock N, Wilson GD, Sanders R. Aggressive basal cell
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carcinoma in young patients: fact or fiction? Br J Plast Surg 2000; 53: 393– 396. 18. Pan ZY, Lin JR, Cheng TT, Wu JQ, Wu WY. In vivo reflectance confocal microscopy of Basal cell carcinoma: feasibility of preoperative mapping of cancer margins. Dermatol Surg 2012; 38: 1945–1950. 19. Peppelman M, Wolberink EA, Blokx WA, van de Kerkhof PC, van Erp PE, Gerritsen MJ. In vivo diagnosis of basal cell carcinoma subtype by reflectance confocal microscopy. Dermatology 2013; 227: 255–262.
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ORIGINAL ARTICLE
Usefulness of in vivo photodiagnosis for the identification of tumor margins in recurrent basal cell carcinoma of the face Riccardo G. Borroni1, Stefania Barruscotti2, Andrea Carugno2, Vincenzo Barbaccia2, Eloisa Arbustini1 & Valeria Brazzelli2
1 Laboratori Sperimentali di Ricerca – Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 2 Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Key words: basal cell carcinoma; fluorescence diagnosis; methylaminolevulinate; photodiagnosis
Correspondence: Valeria Brazzelli, M.D., Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, 27100, Pavia, Italy. Tel: +39 0382 503794 Fax: +39 0382 526379 e-mails: [email protected]; [email protected]
Accepted for publication: 28 January 2015
Funding sources:
SUMMARY Background Basal cell carcinoma (BCC) is the most frequent malignant tumor of the skin. The high prevalence of BCC, the risk of local recurrence, and the difficult clinical identification of the excision margins emphasize the importance of studying new approaches, ensuring complete surgical excision that allows preservation of normal tissue, especially for BCCs located on cosmetically important areas such as the mid face. Photodiagnosis (PD) is a preoperative technique that allows a more accurate distinction of neoplastic lesions from surrounding healthy skin in vivo. Purpose The aim of this study is to assess the usefulness of PD for the evaluation of tumor margins in 10 patients with recurrent BCC of the face. Methods We study the red fluorescence emitted by neoplastic tissue under a Wood’s lamp irradiation, after accumulation of methyl amino levulinate (MAL) cream in 10 patients with recurrent BCC. Results Our histologic analysis of perilesional skin by PD allowed to delineate more precise tumor margins, thus achieving radical excision in 90% of patients. Conclusion PD represents a diagnostic method that helps to distinguish between tumor tissue and surrounding healthy tissue especially in case of recurrent BCC of the face when the clinical delimitation is not clear.
RGB is recipient of the scholarship no. 604 by Fondazione IRCCS ‘San Matteo’, Pavia, titled ‘Terapia fotodinamica topica di precancerosi e carcinomi cutanei in pazienti trapiantati’.
Conflicts of interest: None declared.
Photodermatol Photoimmunol Photomed 2015; 31: 195–201
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12166
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Basal cell carcinoma (BCC) is the most frequent malignant tumor of the skin, and it accounts for 80% of nonmelanoma skin cancer. The incidence is more than 2 million new cases each year worldwide (1). Clinical diagnosis of BCC is straightforward in most cases, and the diagnostic accuracy can be increased by dermoscopy (2). When clinical diagnosis is not certain or when the histologic subtype of BCC may influence the therapeutic approach and the patient’s prognosis, skin biopsy with histologic examination may be required (3). Surgical removal with histologic control of excision margins usually represents the first choice in the treatment of BCC and is the most widely used option with the best outcome (4). Despite careful evaluation of tumor margins, incomplete excision of BCC is common. The recurrence rate after surgical excision of BCC at 5 years is calculated between 4.1% and 10.1% (5). For completely excised lesions with tumor-free resection margins, the 5-year recurrence rate is less than 2% (6) but significantly increases up to 41% in case of incomplete surgical excision (7). The impact of local recurrence is particularly relevant in BCC of the face, especially when lesions are located on the nose, perioral and periauricular regions. Boulinguez et al. showed that 24% of incompletely excised BCCs present with increased aggressive course on recurrence, especially if located in the nasal and periauricular regions (8). Furthermore, the recurrence of BCC after incomplete surgical excision or less effective nonsurgical options may lead to the formation of areas of scar tissue in which recurring BCC may be difficult to distinguish from surrounding healthy skin (4). The high prevalence of BCC, the risk of local recurrence, and the difficult clinical identification of tumor margins emphasize the importance of studying new diagnostic and therapeutic techniques, including exact demarcation of tumor margins ensuring complete surgical excision with preservation of normal tissue, especially for BCCs located on cosmetically important areas such as the mid face. The possibility of using fluorescence for the diagnosis of nonmelanoma skin cancer has been shown in a study conducted in 1998 by Svanberg et al. (9) and also more recently by Stenquist et al. (10) in 2005 and by Tierney et al. (11) in 2011, who have demonstrated the usefulness of in vivo fluorescence imaging in assisting the diagnosis, the treatment, and the follow-up of cutaneous neoplastic lesions. Photodiagnosis (PD), also referred to as fluorescence diagnosis, is a preoperative diagnostic method that
allows a more accurate demarcation of neoplastic lesions in vivo (12). Most commonly used techniques employ precursors of protoporphyrin IX (PpIX), namely d-5aminolaevulinic acid (ALA) and its methyl ester, methyl amino levulinate (MAL), as photosensitizers (13). These are topically applied on the lesional area and are converted into PpIX through the heme biosynthetic pathway (14). The increased activity of the enzyme PBG deaminase and the limited activity of the enzyme ferrochelatase in proliferating tumor cells explain the relatively higher accumulation of PpIX in neoplastic tissue as compared to normal epidermis (15). PpIX is a fluorescent compound with maximum absorption peak around 410 nm (blue) and emission in the spectrum of visible red light (16). Excitation of MAL-treated skin with appropriate wavelengths produces a red fluorescence corresponding to the tumor area, allowing identification of subclinical extent of the tumor. The aim of this study was to assess the usefulness of PD for the evaluation of tumor margins in 10 patients with recurrent BCC of the face, in which the clinical demarcation of tumor margins was difficult and not clear.
196
Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PATIENTS AND METHODS Ten patients (four male and six female) presenting a clinical and histologic diagnosis of recurrent BCC of the face were included in this study. The age of the patients ranged from 44 to 78 (mean 70.4). Nine patients had a recurrence of BCC in the scar of the previous surgical excision, and one patient had a recurrence of BCC that had been previously treated with cryotherapy. Seven of the BCCs occurred on the nose, two on the forehead, and one on the scalp. According to histology of primary BCC excision, patients were affected by recurrence of six morpheiform subtype of BCC (60%), three superficial BCC (30%), and one pigmented BCC (10%). Clinical data were recorded for each patient, including relevant medical history with particular interest to comorbidities, concomitant medications, age, gender, anatomic site of skin lesions, and size of the lesional area. Clinically visible margins of each skin lesion were drawn with a dermographic pen, and the surface of each skin area was measured. Methyl-aminolevulinate (MAL) 160 mg/g cream (Metvix, Galderma Italia, Milano, Italy) was applied in a 1-mm thick layer, extending the application to clinically uninvolved skin in a range of 10 mm around the lesion. The area involved was then covered with a photo-opaque dressing to prevent the exposure to light
Photodiagnosis in recurrent BCCs of the face
and sealed for 3 h. After 3 h, the MAL film was removed, the excess cream was gently wiped off, and the lesion was irradiated using a Wood’s lamp (Philips TL8W/08) in a dark room. The margins of the lesional area emitting an intense red fluorescence were then drawn with a dermographic pen to obtain a clear demarcation between the tumor and the surrounding healthy skin, which was characterized by a dim red fluorescence (‘gray zone’). The margins were also reported on graph paper to calculate the lesional area and to apply it onto the surgical site pre-operatively. Clinical and fluorescence pictures were taken, respectively, before and during PD with a digital camera, positioned on a tripod at a distance of 40 cm from the skin. The surface of the fluorescent red area was measured and compared with the surface of the clinical area. To support the hypothesis of the absence of BCC in the dim fluorescent area, 4-mm punch skin biopsies for histopathological evaluation were taken in this ‘gray zone’ for each patient (Figs 1 and 2). In case of BBC negative in biopsies performed in the gray area, the margins of surgical excision corresponded to the margins of the red area. In case of positive result of histologic biopsies performed in the gray area, the surgical margins have been expanded extending beyond the BCC-positive site of biopsy.
According to the result of the data obtained with the red fluorescence imaging of the tumor area and the histologic result of skin biopsies outside the red area, surgical margins were drawn and a surgical excision of BCC subsequently was planned within a week. All patients gave written informed consent for participating to the study, which was conducted in accordance with the Declaration of Helsinki principles and was approved by the Ethics Committee of the Fondazione IRCCS Policlinico San Matteo of Pavia, Italy.
RESULTS Ten patients with ‘problematic’ BCC because of the number of recurrence, the location on the face, and the difficulties in defining the tumor margins were included in the study. In seven patients (70%), the BCC occurred on the nose, in two (20%) on the forehead, and in one (10%) on the scalp. Tumor area delimited by clinically visible margins ranged between 1.5 and 10 cm2 (mean area 3.68 3.29 cm2, Table 1). The tumor area evaluated by measurement of the bright red fluorescence evident with PD ranged from 1.73 cm2 to 14.75 cm2 (mean area 4.67 4.08 cm2, Table 1). A total of 29 biopsies in the ‘gray zone’ were performed (average of 2.9 biopsies for each patient),
(a)
(b)
(c)
(d)
Fig. 1. Patient 2, recurrence of BCC on left nasal ala after repeated cryotherapy sessions, (a) clinical presentation of the lesion on recurrence; (b) affected area illuminated with Wood lamp during PD; red arrow and gray arrow indicate ‘red’ zone and ‘gray’ zone, respectively; (c) Drawing of margins of the affected area after PD with biopsies site (small circles outside the ‘red area’); (d) drawing on graph paper of the clinically visible lesion (dotted line) of ‘red’ area (solid line) and ‘gray’ area (dashed line). Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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(a)
(b)
(c)
(d)
Fig. 2. Patient 4, recurrence of BCC on right nasal tip, (a) clinical aspect of the lesion at presentation; the dotted line indicates the area where MAL cream will be applied; (b) affected area illuminated with Wood lamp during PD; ‘red’ zone (red arrow) and ‘gray’ zone (gray arrow) are evident; (c) the drawing of margins of the affected area with biopsies site; (d) drawing on graph paper of the clinically definable lesion (dotted line) of ‘red’ area (solid line) and ‘gray’ area (dashed line).
depending on the size of the measured area, its location, and the more or less clear demarcation of the bright red area. Biopsies performed in the less fluorescent area confirmed the absence of neoplastic cells out of the red area in eight patients: 25 of 29 biopsies (86.2%) were free from BCC. Biopsies performed in the less fluorescent area were infiltrated by BCC in two patients (three biopsies in one patient and one biopsy in the other showed the presence of tumor cells): four of 29 biopsies (17.8%) were infiltrated by BCC (Table 1). Areas of surgical excision were obtained by integrating the results of the PD and histology and corresponded to the red area determined with PD in eight of 10 patients (80%), and in the remaining two patients (20%), the area has been enlarged compared to the red fluorescence, beyond BCC-positive site of biopsies. Surgical excision of all 10 BCC was then performed: for one patient (10%), the histologic evaluation of the area excised showed involvement of BCC in a resection margin, while in the other nine patients (90%), the surgical margins were not involved and BCC was completely excised.
DISCUSSION Complete excision of BCC should always be the goal of surgical treatment; however, incomplete excision of BCC 198
is frequent. Reported rates of incomplete excision after routine excision range from 1.9% to 16% (4). Recently, Walker and Hill reviewed 5-year follow-up studies and found an average of 38% recurrence rate (range 19– 100%) after incomplete BCC excision (6). Milroy and colleagues suggested that the aggressive behavior of BCCs may follow inadequate excision due to diagnostic uncertainty and cosmetic concerns (17). Factors contributing to incomplete excision include difficult to identify tumor margins, especially when prior surgical and nonsurgical treatments have altered tissue architecture, particularly evident after re-excision of flap repairs causing distortion of tissue planes and loss of tissue reservoirs used for the initial flap, often resulting in a large defects with limited repair options (4). Mohs micrographic surgery (MMS) has been shown to the most effective modality for removing high-risk BCCs located on the mid face and the ears. MMS has been demonstrated to have superior initial, 5-year recurrence rates, and cosmetic outcomes as compared to other treatment modalities, however, is expensive and requires long processing time. In the last years, in vivo reflectance confocal microscopy (RCM) has proven to be useful, noninvasive in vivo technique for real-time imaging of the epidermis and superficial dermis. RCM has been reported to be useful in the in vivo evaluation of skin tumors such as Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Photodermatol Photoimmunol Photomed 2015; 31: 195–201 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
M, 44
F, 67
F, 79
M, 74
F, 75
M, 69
F, 78
F, 75
M, 72
2
3
4
5
6
7
8
9
10
Nasal dorsum
Left nasal pyramid
Right temple
Scalp
Left ala
Nasal dorsum
Right nasal tip
Nasal dorsum
Left ala
Right forehead
Anatomic Site
Pigmented BCC recurrence
Morpheiform BCC recurrence
Superficial BCC recurrence
Morpheiform ulcerated BCC recurrence Morpheiform BCC recurrence
Morpheiform BCC recurrence
Morpheiform BCC recurrence
Superficial BCC recurrence
Morpheiform ulcerated BCC recurrence Superficial BCC recurrence
Diagnosis
29
2
2
3
4
25 free, 4 infiltrated
2 free
1 free 1 infiltrated
3 free
4 free
3 free
3 free
3
3
2 free
3 free
3 free
3 infiltrated 1 free
Histologic result of biopsies
2
3
3
4
N° biopsies
BCC, basal cell carcinoma; F, female; M, male; and PD, photodiagnosis.
70.4 10.0
F, 71
1
Patient (sex, age) Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Completely excised BCC with free resection margins Superficial BCC present in occasional microfoci of a resection margin Completely excised BCC with free resection margins Completely excised BCC with free resection margins 9 Completely excised BCC, 1 BCC present in a resection margin
Surgical excision of BCC
Table 1. Demographic and clinic-pathological features of patients, with recurrent BCC of the face
3.50
3.00
1.75
1.50
8.75
2.50
3.70
4.45 4.67 4.08
2.00
2.80
4.00 3.68 3.29
2.25
2.00
10.00
2.00
1.75
1.75
14.75
9.50
1.50
Size of PD area, (mm2)
Size of the clinical evident BCC area, (mm2)
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melanoma, squamous cell carcinoma, and BCC (18). The main limiting factors of this technique are • The limited depth of RCM penetration. • The requirement that the surface of the lesion margins is flat enough for examination. and • The presence of hyperkeratosis, thickness, or the anatomic site of lesions may make examination difficult or misleading. RCM can still be time consuming, and it requires well-trained medical staff, and, currently, the RCM device is particularly expensive (19). Alternative options to MMS or RCM may be necessary in settings where these techniques are not available and to have a good quality of surgical excision with cost-efficiency of the treatments. PD is a simple, noninvasive pre-operative investigation that allows a more accurate demarcation of neoplastic lesions and can help in increasing the efficiency of surgical excision. PD can be decisive in difficult cases of recurrent BCC, especially when the presence of scar tissue makes it difficult for the delimitation or when tumors are located in difficult sites, such as the face (12). In our study, we used PD to delineate tumor margins of clinically poorly defined, recurrent BCC of the face. By performing multiple punch skin biopsies in the dim fluorescent area surrounding the site of higher fluorescence, we demonstrate that PD can help the clinician to better define tumor margins. Biopsies performed in the area surrounding the site of higher fluorescence showed the absence of neoplastic cells in 86.2% of cases. In 17.8% of biopsies performed on the less fluorescent areas, however, biopsies showed recurrence of BCC. This could be explained by scar from previous incomplete
surgical excisions that could have hampered tissue penetration of MAL. Despite positivity of some skin biopsies performed in the ‘gray zone’, this result has allowed the surgeon to draw with good security the tumor margins and achieve radical excision in 90% of cases. The red fluorescent image obtained with PD, along with the histologic results of the biopsies in the less fluorescent area, allowed to remove all the BCC with a secure demarcation of tumor margins and gave information about the enlargement of the margins displayed with the PD. Our histologic analysis of perilesional skin by PD, allowed to delineate more precise tumor margins, thus achieving radical excision in the majority of patients. Although thise is a method that takes time, effort, and accuracy, it has allowed us to get a good result, with regard to the radicality. In the future, we plan to perform larger studies without histologic examination to reduce potential harm to cosmetically important areas of the face and limit procedure costs. In conclusion, in our cases, both PD and biopsy results together have represented a diagnostic method to obtain a clear distinction between the tumor tissue and the surrounding healthy tissue that were not possible with the only clinical diagnosis. In case of difficult BCCs, especially when recurrent or in difficult sites, where the presence of scar tissue makes it difficult to delimitate, and also the RCM would give unreliable results, PD with biopsies can increase up to 90% the percentage of completed excision of this type of tumors. In addition, our work, defining an area of intense red fluorescence that corresponds to the tumor area, suggests a future possibility of PD examination to guide the definitions of margins in primary BCC.
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