- Email: [email protected]
Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: Case series and review of the literature
EJSO 33 (2007) 364e369
www.ejso.com
Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: Case series and review of the literature C. Renzi a,*, A. Caggiati b, T.J. Mannooranparampil a, F. Passarelli c, G. Tartaglione d, G.M. Pennasilico e, S. Cecconi e, C. Potenza b, P. Pasquini a a b
Clinical Epidemiology Unit, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy Department of Plastic Surgery, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy c Pathology Department, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy d Department of Nuclear Medicine of the Ospedale Cristo Re, Via Monti di Creta, 104, 00167 Rome, Italy e Radiology Department, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy Accepted 11 October 2006 Available online 28 November 2006
Abstract Aims: Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer. The metastatic potential is generally low. However, there are subgroups of patients at higher risk, for whom sentinel lymph node biopsy (SLNB) might be useful. SLNB might allow the timely inclusion of high risk patients in more aggressive treatment protocols, sparing at the same time node-negative patients the morbidity of potentially unnecessary therapy. Our aim was to introduce the concept of SLNB for patients with high risk cutaneous SCC. Patients and methods: We examined a consecutive series of high risk cutaneous SCC patients undergoing SLNB at our large dermatological hospital, and performed a literature review and pooled analysis of all published cases of SLNB for cutaneous SCC. Results: Among the 22 clinically node-negative patients undergoing SLNB at our hospital, one patient (4.5%) showed a histologically positive sentinel node and developed recurrences during follow-up. Sentinel node-negative patients showed no metastases at a median followup of 17 months (range: 6e64). The incidence of positive sentinel nodes in previous reports ranged between 12.5% and 44.4%. Pooling together patients from the present and previous studies (total 83 patients), we calculated an Odds Ratio of 2.76 (95% CI 1.2e6.5; p ¼ 0.02) of finding positive sentinel nodes for an increase in tumor size from <2 cm to 2.1e3 cm to >3 cm. Conclusions: Our case series and the pooled analysis support the concept that SLNB can be performed for high risk cutaneous SCC. Prospective multicenter studies are needed to examine the role, utility and cost-effectiveness of SLNB for this population. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Sentinel lymph node biopsy; Cutaneous squamous cell carcinoma; Case series and review
Introduction Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer. The incidence rate in western countries is 71.2 per 100 000 person years among women and 155.5 per 100 000 among men, with an increase in the age-adjusted incidence of 50e200% over the past 10e30 years.1e3
* Corresponding author. Tel.: þ39 06 66464482; fax: þ39 06 66464307. E-mail address: [email protected] (C. Renzi). 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.10.017
In the majority of cases of cutaneous SCC the risk of developing metastasis is low, with an overall five-year metastatic rate of 5%.1 However, there are subgroups of patients at higher risk, depending on patient and tumor characteristics.3e7 For example, metastatic rates are 30% for lesions > 2 cm in diameter.1 Risk factors for metastasis include tumor size and location, locally recurrent SCC or arising on chronically diseased skin, poorly differentiated histologic subtype, perineural invasion, depth > 4 mm, involvement of the reticular dermis or subcutaneous fat or penetration into muscle, bone or cartilage and immunosuppression.1,5
C. Renzi et al. / EJSO 33 (2007) 364e369
Various factors influence the management of cutaneous SCC, such as the treatment of the primary lesion, the risk of lymph node metastases8 and patient related factors (age, co-morbidity, and patients’ preferences). Sentinel lymph node biopsy (SLNB) has been shown to be important in the staging of malignant melanoma and other solid tumors.9e12 Use of SLNB for cutaneous SCC is at an early stage, with only few studies having been published on a limited number of patients.13e17 These studies suggest that SLNB might be useful for high risk SCCs. Most patients with lymph node metastasis are curable, however, a minority will die, despite treatment. Among patients with operable, metastatic, cutaneous SCC of the head and neck the five-year disease-free survival rate is approximately 70e75%, despite treatment.18 Early identification of micrometastasis could allow the selective and timely inclusion of high risk patients in more aggressive treatment and follow-up protocols, with potential survival benefits. At the same time SLNB could spare node-negative patients the morbidity of potentially unnecessary additional therapy. The aim of our study is to introduce the concept of SLNB for patients with high risk cutaneous SCC, by reporting on a case series of high risk cutaneous SCC undergoing SLNB at our hospital and performing a critical review and pooled analysis of all published cases of SLNB for cutaneous SCC. Patients and methods Case series A total of 22 patients with high risk cutaneous SCC, clinically node-negative, underwent SLNB, between 1998 and 2005, at the Plastic Surgery Department of the Istituto Dermopatico dell’Immacolata (IDI), a large dermatological hospital in Italy. The mean age of patients was 64.2 years (standard deviation (SD) 13.8; range: 35e80 years) and 86.4% were men. Patients were identified as having high metastatic risk, if presenting any of the risk criteria reported in the literature.1,5 In particular, 14 patients had lesions > 2 cm in diameter, 12 patients had SCCs infiltrating the subcutis, bone or muscles, 10 SCCs were >4 mm in depth, 15 SCCs were located at high risk sites, such as lower lip or lip commissure (n ¼ 13) and ear (n ¼ 2), 10 patients had poorly or moderately differentiated SCCs, two SCCs showed perineural infiltration and three patients had recurrent tumors. No patient was immunosuppressed. Among included patients, 73% (n ¼ 16) responded to three or more high risk criteria. Mean tumor size was 2.7 cm (median: 2.4 cm; range: 1.0e6.7 cm). Patients with genital SCC and clinical signs of metastasis were excluded. Follow-up visits and lymph node ultrasound examinations were scheduled every six months during the first two years after surgery and once a year thereafter. When patients could not be visited at our hospital, follow-up
365
information was obtained from medical records and telephone interviews. The study was approved by the institutional ethical committee and written informed consent was obtained from participating patients. Lymphoscintigraphy was performed after injecting 30e50 MBq of Technetium-99m radiolabelled nanocolloid at the site of the tumor. Static and dynamic acquisition was started immediately after the injection and the skin projection of the sentinel lymph node (SLN) was marked with ink. After 3e18 h, surgical removal of the primary tumor and SLNB were performed at the plastic surgery department, using a handheld gamma camera for the detection of the SLN. The primary lesion was excised first, before performing the SLNB, in order to prevent ‘‘shine-through’’. Radiolocalization was combined with intradermal injection of vital blue dye at the primary tumor site at the beginning of the surgical procedure. For head and neck tumors blue dye was not used, because, in our experience, for this location it is less effective, probably due to the rapid lymphatic wash-out, and it can cause permanent facial tattooing.19 Using these techniques on melanoma patients, our SLN detection rate is 97.4%,20 which is in agreement with the literature.21 The sentinel node radiolocalization technique, applied to the first patients with cutaneous SCC treated at our hospital, was previously described.19,22 The present study, examining the histologic and clinical characteristics associated with SLN positivity, includes the complete series of patients with high risk cutaneous SCC recruited at our hospital. Surgical excision of the primary tumors has been performed removing wide margins, with tissue margins examined histologically, following international guidelines.8 SLNs were sectioned at 3 mm intervals and included in paraffin. Ten 5-mm sections were then obtained and examined using hematoxylineeosin and immunohistochemical staining with anticytokeratin antibodies (MNF116 DAKO). Literature review and pooled analysis We carried out a review of the literature on SLNB for cutaneous SCC. The Medline, Ovid and Cochrane Library databases were searched using the following terms: sentinel lymph node, squamous cell carcinoma, cutaneous, skin, lip; accepted publication languages were English, French, German, Italian and Spanish. We contacted the authors of the studies asking for additional information on clinical and histopathological characteristics of included cases, but no further data were obtained. Cases of SLNB for cutaneous SCC were tabulated and a pooled analysis, including also our new cases, was performed. ManteleHaenszel Odds Ratios (OR) and 95% Confidence Intervals (95% CI) were calculated for the association between tumor size (categorized in 2 cm, 2.1e3 cm and >3 cm) and positive SLN.
366
C. Renzi et al. / EJSO 33 (2007) 364e369
Moreover, multiple logistic regression was used for examining the independent effect on the likelihood of SLN metastases of tumor size and of perineural, vascular, bone, cartilage or muscle infiltration, controlling for patient age. Because detailed information on infiltration was not consistently reported for sufficient numbers of patients, in order to avoid excessively sparse data, a summary variable was created, i.e. infiltration of any of the previously mentioned structures versus no infiltration. We used the computer package STATA-9.0 for Windows for statistical analyses. Results Case series Among the 22 patients treated at IDI, lymphoscintigraphy identified 41 SLNs (median: 1.8 nodes per patient; range: 1e4). SLNB was performed under general anesthesia in nine patients and with local anesthesia with mild intravenous sedation in 13 patients. Patients were discharged within the second day after surgery. We observed two minor complications, i.e. two cases of dehiscence of the surgical wound in tumors of the lip, not requiring further surgical procedures. We did not observe any other complications. Of the 41 SLNs examined by means of immunostaining, one positive node was found among a 70-year-old man, with an SCC of the left foot (fifth toe). The ulcerated tumor had a diameter of 2.5 cm and at histopathology it was poorly differentiated, it showed vascular, perineural and bone infiltration and tumor depth was >4 mm. The positive lymph node was detected in the left inguinal basin. At radical lymph node dissection of the involved basin one node was positive for metastasis from SCC. Four months after the initial surgery, the SCC had infiltrated the left foot, at the base of the amputated toe, and showed in-transit metastasis on the thigh. Moreover, lymph node metastases were noted in the contralateral inguinal basin at ultrasound and were confirmed by histological examination. Subsequently the patient started chemotherapy. Clinical and ultrasound examinations performed before surgery in this patient had not shown any enlarged lymph nodes nor any signs of potential metastases. Overall, the median follow-up was 17 months (range: 6e64 months). Of the 21 patients with no evidence of micrometastases at SLNB, 17 are still alive, without clinical signs of tumor spread. One patient had a local recurrence. Four patients died during follow-up, between 76 and 82 years of age, due to causes not related to the SCC (e.g. stroke, lung cancer, etc.). Literature review and pooled analysis We identified 11 papers reporting SLNB for cutaneous SCC.13e17,23e28 Six of them 23e28 are reports of single
cases. Two studies14,15 included also some patients with genital or perineal SCCs. These patients were excluded from our analyses. Summary information on the studies and characteristics of patients with positive SLNs are reported in Table 1. The biggest study included 20 patients with SCC of the lower lip,16 but SLN were identified only on 18 of them. Proportions of positive SLNs in the literature range between 12.5% and 44.4%. Pooling together patients from all published studies and from our case series (total 83 patients) showed that the greatest number of SLN biopsies was performed on SCCs of the lower lip (n ¼ 36), followed by SCCs of the face (excluding lip and ear) (n ¼ 10) and SCCs of the leg (excluding foot) (n ¼ 10). Among patients with a tumor at the lower lip, face and leg, positive SLNs were found in 8.3% (n ¼ 3), 30% (n ¼ 3) and 20% (n ¼ 2), respectively. Overall, among the 83 patients, 16.9% (n ¼ 14) had positive SLNs (95% CI: 9.5e26.7). All patients with positive SLNs had lesions > 2 cm in diameter (Table 1). Among patients with tumors 2 cm, 2.1e3 cm and >3 cm in diameter, proportions of positive SLNs were 0%, 15.8% and 30.4%, respectively (Fisher’s exact, p ¼ 0.058). An increase in tumor size from 2 cm to 2.1e3 cm to >3 cm was associated with a 2.8-fold higher odds of finding positive SLN (ManteleHaenszel OR ¼ 2.76; 95% CI 1.2e6.5; p ¼ 0.02). Furthermore, multiple logistic regression has shown that tumor size is significantly associated with a higher likelihood of positive SLNs (OR ¼ 4.27; 95% CI 1.2e15.3; p ¼ 0.026), independently of vascular, perineural, bone or muscle infiltration and of patient age. Infiltration and age showed no significant association with SLN status. Discussion Our case series and review of the literature have shown that SLNB has recently started to be used in selected cases of high risk cutaneous SCC, and our results support the concept that it can be applied for staging of high risk cutaneous SCC. However, our report also highlights the need of rigorous prospective multicentre studies, before being able to draw any conclusions. In fact, published studies on SLNB for cutaneous SCC and our present case series are all based on limited numbers of patients and short follow-up times. The small sample size can lead to marked differences in the results, simply due to sampling variation. This might partially explain the discordance between the relatively high proportions of positive SLNs for cutaneous SCCs reported in the literature,13e17 compared to our case series. Furthermore, our review is limited by the lack of uniform criteria for defining high risk patients. This reflects the fact that evidence is lacking particularly regarding the risks associated with the simultaneous presence of multiple
C. Renzi et al. / EJSO 33 (2007) 364e369
367
Table 1 Positive sentinel lymph node (SLN) biopsies for cutaneous SCC reported in the literature and characteristics of patients with positive sentinel nodes Study
No. of SLNþ pts/total pts studied (%)
Age of SLNþ pts
Tumor location of SLNþ pts
Tumor size of SLNþ pts (cm)
Tumor depth of SLNþ pts
Michl, 2003
2/9 (22.2)
52 78
Presternal Lower leg
9.0 5.0
Reschly, 2003
4/9 (44.4)
73 66 41 45
Wrist Lower leg Clavicle Scalp
4.5 11.0 3.0 3.5
>4 mm >4 mm >4 mm >4 mm
Nouri, 2004
1/8 (12.5)
n.a.
Face
n.a.
n.a.
Wagner, 2004
2/11 (18.2)
66 93
Face Face
Altinyollar, 2002
3/18 (16.6)
n.a. n.a. n.a.
Lower lip Lower lip Lower lip
Stadelmann, 1997 Weisberg, 2000 Perez-Naranjo, 2005 Ardabili, 2003 Yamada, 2004 Ozcelik, 2004
1/1 0/1 0/1 0/1 0/1 0/1
72
Renzia
1/22 (4.5)
70
Subcutis Deep dermis
4.5 3.0
n.a. n.a.
>2.0 >2.0 >2.0
n.a. n.a. n.a.
Wrist
4.0
n.a.
Foot
2.5
>4 mm
SLN ¼ sentinel lymph node; pts ¼ patients; and n.a. ¼ not available. a IDI case series.
risk factors. Unfortunately, no study until now has had sufficient power to examine, in multivariate analysis, the independent effect of each factor (and interaction between factors) on the risk of recurrence and metastasis. For example, tumor size has been shown to be an important risk factor for metastasis, but different definitions and cut-offs have been used: a commonly used cut-off size is >2 cm,1,8 whereas the National Comprehensive Cancer Network (NCCN) guidelines29 group together tumor size and location as one risk factor, with size being divided into three categories such as 6 mm, 10 mm, 20 mm, depending on tumor location. Among the reviewed studies, somewhat different cutoffs regarding tumor size were used for identifying high risk patients: one study15 included SCCs > 1 cm, if located on face and distal extremities, or >4 cm for trunk and proximal extremities; other studies13,17 included SCCs > 2 cm for all locations (except lip or ear, that were considered high risk independently of size); other authors included only SCCs 4 cm.14 It should be highlighted, that the majority of included patients presented also other high risk factors, in addition to size and location, e.g. infiltration of the deep dermis, subcutis, muscles or bone, poor differentiation, etc. Similarly, in our case series, more than 70% of patients responded to three or more high risk criteria. Considering the uncertainty on the best definition for high risk patients and the still preliminary data on SLNB for cutaneous SCC, a conservative approach for future
studies could be, for example, including patients with at least two or three high risk factors. The pooled analysis has shown that an increase in tumor size from 2 cm to 2.1e3 cm to >3 cm is associated with a ManteleHaenszel OR of 2.8 of finding lymph node micrometastasis. This is in agreement with studies on clinically evident metastases, reporting a three times higher metastatic risk for tumors > 2 cm compared to smaller tumors.5 It is, however, noteworthy, that recent studies on head and neck cutaneous SCCs18 have shown that also relatively small lesions (<2 cm) are at risk of lymph node metastasis, particularly if thickness is 4 mm. This suggests that size alone is probably a weak independent predictor of metastases and other factors, particularly thickness, should also be considered.18,30 Our study, including both head and neck and non-head and neck SCCs, had limited power for examining the effect of other risk factors, such as depth of infiltration, perineural or vascular infiltration and specific tumor locations. Previous studies have shown that most metastatic lymph nodes from head and neck cutaneous SCCs occur in the parotid gland.18 Unfortunately, in our series, SCCs located on or around the external ear and the frontotemporal scalp, which can metastatize to lymph nodes within the parotid, with or without involvement of cervical nodes,18 are underrepresented. In our series, the majority of patients had SCCs of the lip or lip commissure. Despite being usually considered high risk, none showed positive SLNs. The small number of patients in our series with lesions located near the
368
C. Renzi et al. / EJSO 33 (2007) 364e369
parotid and the fact that some important risk factors, such as recurrent SCCs or immunosuppression, were underrepresented, limits the generalizability of our results and might partially explain the lower than expected SLN positivity. Further studies, looking specifically at cutaneous SCCs with high risk characteristics located in the parotid drainage area, might show higher incidence of positive SLNs. Large, multicenter studies with at least five-year followup are needed for examining the independent effect of specific risk factors on the probability of positive SLNs by means of multivariate analysis and for evaluating the role and cost-effectiveness of sentinel lymph node biopsy for high risk cutaneous SCC.21 It has been suggested that SLNB might have a greater potential of controlling metastatic dissemination among patients with cutaneous SCC compared to melanoma patients, because SCCs tend to metastasis mainly to regional lymph nodes and because of their radiosensitivity.13 In any case, all patients with high risk SCC should be followed-up closely. Studies have shown that the majority of recurrences and metastases take place within two years after treatment, with 95% of recurrences and metastases being observed within five years. Thus, close follow-up is essential during this period of time to detect recurrences, metastases and also new primary skin cancers.1,4,29 High risk individuals should undergo screening once or twice yearly and, whenever possible, patients should be instructed in self-examination and use of sunscreens.1,8 In conclusion, our report supports the concept that SLNB can be applied for high risk cutaneous SCC. Large, multicenter, longitudinal studies are needed to further evaluate clinical and histopathological characteristics associated with positive SLNs and the cost-effectiveness of SLNB in patients with high risk cutaneous SCC. These studies could be particularly valuable, considering the increasing incidence of cutaneous SCC.
Acknowledgements We would like to thank N. Melo Salcedo and S. Bolli for assisting in the data collection and data entry. The study was financially supported by the Italian Ministry of Health. The authors have no conflict of interest to disclose.
References 1. Alam M, Ratner D. Cutaneous squamous cell carcinoma. N Engl J Med 2001;344:975–83. 2. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK. Trends in the population based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992. Arch Dermatol 1997;133:735–50. 3. Rudoph R, Zelac D. Squamous cell carcinoma of the skin. Plast Reconstr Surg 2004;114:82–94.
4. Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 2002;28: 268–73. 5. Rowe D, Carroll R, Day C. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 1992;26:976–90. 6. Fernandez-Angel I, Rodriguez-Archilla A, Aneiros Cachaza J, Munoz Medina M, Serrano Ortega S. Markers of metastasis in lip cancer. Eur J Dermatol 2003;13:276–9. 7. Schwartz RA, Stoll HL. Squamous cell carcinoma. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. 4th ed., Dermatology in general medicine, vol. 1 New York: McGraw-Hill; 1993, p. 821–39. 8. Motley R, Kersey P, Lawrence C. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Plast Surg 2003;56:85–91. 9. Kell MR, Kerin MJ. Sentinel lymph node biopsy. BMJ 2004;328: 1330–1. 10. Berk DR, Johnson DL, Uzieblo A, Kiernan M, Swetter SM. Sentinel lymph node biopsy for cutaneous melanoma. Arch Dermatol 2005; 141:1016–22. 11. McMasters KM, Noyes RD, Reintgen DS, et al. Lessons learned from the sunbelt melanoma trial. J Surg Oncol 2004;86:212–23. 12. Morton DL. Interim results of the multicenter selective lymphadenectomy trial (MSLT-I) in clinical stage I melanoma. In: Presented at the American Society of Clinical Oncology, Orlando, FLA; May 14, 2005. Available at: http://www.asco.org. 13. Reschly MJ, Messina J, Zaulyanov L, Cruse W, Fenske N. Utility of sentinel lymphadenectomy in the management of patients with highrisk cutaneous squamous cell carcinoma. Dermatol Surg 2003;29: 135–40. 14. Wagner JD, Evdokimow DZ, Weisberger E, et al. Sentinel node biopsy for high-risk nonmelanoma cutaneous malignancy. Arch Dermatol 2004;140:75–9. 15. Michl C, Starz H, Bachter D, Balda B-R. Clinical and laboratory investigations Sentinel lymphonodectomy in nonmelanoma skin malignancies. Br J Dermatol 2003;149:763–9. 16. Altinyollar H, Berberoglu U, Celen O. Lymphatic mapping and sentinel lymph node biopsy in squamous cell carcinoma of the lower lip. Eur J Surg Oncol 2002;28:72–4. 17. Nouri K, Rivas MP, Pedroso F, Bhatia R, Civantos F. Sentinel Lymph node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck. Arch Dermatol 2004;140:1284. 18. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck. Cancer 2006;106:2389–96. 19. Tartaglione G, Potenza C, Caggiati A, et al. Lymphatic mapping and sentinel node identification in squamous cell carcinoma and melanoma of the head and neck. Tumori 2002;88:S39–41. 20. Caggiati A, Migliano E, Potenza C, et al. Sentinel node biopsy for malignant melanoma. Technical details and clinical results on 390 patients. Minerva Chir 2002;57:481–7. 21. Swan MC, Furniss D, Cassell OC. Surgical management of metastatic inguinal lymphadenopathy. BMJ 2004;329:1272–6. 22. Tartaglione G, Potenza C, Caggiati A, Gabrielli F, Russo A, Pagan M. Sentinel node radiolocalisation and predicative value in lip squamous cell carcinoma. Radiol Med 2003;106:256–61. 23. Stadelmann WK, Javaheri S, Cruse CW, Reintgen DS. The use of selective lymphadenectomy in squamous cell carcinoma of the wrist: a case report. J Hand Surg 1997;22:726–31. 24. Weisberg NK, Bertagnolli MM, Becker DS. Combined sentinel lymphadenectomy and Mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2000;43(3): 483–8. 25. Perez-Naranjo L, Herrera-Saval A, Garcia-Bravo B, Perez-Bernal AM, Camacho F. Sentinel lymph node biopsy in recessive dystrophic epidermolysis bullosa and squamous cell carcinoma. Arch Dermatol 2005;141:110–1.
C. Renzi et al. / EJSO 33 (2007) 364e369 26. Ardabili M, Gambichler T, Rotterdam S, Altmeyer P, Hoffmann K, Stucker M. Metastatic cutaneous squamous cell carcinoma arising from a previous area of chronic hypertrophic lichen planus. Dermatol Online J 2003;9:10. 27. Yamada M, Hatta N, Sogo K, Komura K, Hamaguchi Y, Takehara K. Management of squamous cell carcinoma in a patient with recessivetype epidermolysis bullosa dystrophica. Dermatol Surg 2004;30: 1424–9.
369
28. Ozcelik D, Tatlidede S, Hacikerim S, Ugurlu K, Atay M. The use of sentinel lymph node biopsy in squamous cell carcinoma of the foot: a case report. J Foot Ankle Surg 2004;43:60–3. 29. Miller SJ. The National comprehensive cancer network (NCCN) guidelines of care for nonmelanoma skin cancers. Dermatol Surg 2000;26:289–92. 30. Veness MJ. Defining patients with high-risk cutaneous squamous cell carcinoma. Australas J Dermatol 2006;47:28–33.
www.ejso.com
Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: Case series and review of the literature C. Renzi a,*, A. Caggiati b, T.J. Mannooranparampil a, F. Passarelli c, G. Tartaglione d, G.M. Pennasilico e, S. Cecconi e, C. Potenza b, P. Pasquini a a b
Clinical Epidemiology Unit, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy Department of Plastic Surgery, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy c Pathology Department, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy d Department of Nuclear Medicine of the Ospedale Cristo Re, Via Monti di Creta, 104, 00167 Rome, Italy e Radiology Department, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Via Monti di Creta, 104, 00167 Rome, Italy Accepted 11 October 2006 Available online 28 November 2006
Abstract Aims: Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer. The metastatic potential is generally low. However, there are subgroups of patients at higher risk, for whom sentinel lymph node biopsy (SLNB) might be useful. SLNB might allow the timely inclusion of high risk patients in more aggressive treatment protocols, sparing at the same time node-negative patients the morbidity of potentially unnecessary therapy. Our aim was to introduce the concept of SLNB for patients with high risk cutaneous SCC. Patients and methods: We examined a consecutive series of high risk cutaneous SCC patients undergoing SLNB at our large dermatological hospital, and performed a literature review and pooled analysis of all published cases of SLNB for cutaneous SCC. Results: Among the 22 clinically node-negative patients undergoing SLNB at our hospital, one patient (4.5%) showed a histologically positive sentinel node and developed recurrences during follow-up. Sentinel node-negative patients showed no metastases at a median followup of 17 months (range: 6e64). The incidence of positive sentinel nodes in previous reports ranged between 12.5% and 44.4%. Pooling together patients from the present and previous studies (total 83 patients), we calculated an Odds Ratio of 2.76 (95% CI 1.2e6.5; p ¼ 0.02) of finding positive sentinel nodes for an increase in tumor size from <2 cm to 2.1e3 cm to >3 cm. Conclusions: Our case series and the pooled analysis support the concept that SLNB can be performed for high risk cutaneous SCC. Prospective multicenter studies are needed to examine the role, utility and cost-effectiveness of SLNB for this population. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Sentinel lymph node biopsy; Cutaneous squamous cell carcinoma; Case series and review
Introduction Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer. The incidence rate in western countries is 71.2 per 100 000 person years among women and 155.5 per 100 000 among men, with an increase in the age-adjusted incidence of 50e200% over the past 10e30 years.1e3
* Corresponding author. Tel.: þ39 06 66464482; fax: þ39 06 66464307. E-mail address: [email protected] (C. Renzi). 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.10.017
In the majority of cases of cutaneous SCC the risk of developing metastasis is low, with an overall five-year metastatic rate of 5%.1 However, there are subgroups of patients at higher risk, depending on patient and tumor characteristics.3e7 For example, metastatic rates are 30% for lesions > 2 cm in diameter.1 Risk factors for metastasis include tumor size and location, locally recurrent SCC or arising on chronically diseased skin, poorly differentiated histologic subtype, perineural invasion, depth > 4 mm, involvement of the reticular dermis or subcutaneous fat or penetration into muscle, bone or cartilage and immunosuppression.1,5
C. Renzi et al. / EJSO 33 (2007) 364e369
Various factors influence the management of cutaneous SCC, such as the treatment of the primary lesion, the risk of lymph node metastases8 and patient related factors (age, co-morbidity, and patients’ preferences). Sentinel lymph node biopsy (SLNB) has been shown to be important in the staging of malignant melanoma and other solid tumors.9e12 Use of SLNB for cutaneous SCC is at an early stage, with only few studies having been published on a limited number of patients.13e17 These studies suggest that SLNB might be useful for high risk SCCs. Most patients with lymph node metastasis are curable, however, a minority will die, despite treatment. Among patients with operable, metastatic, cutaneous SCC of the head and neck the five-year disease-free survival rate is approximately 70e75%, despite treatment.18 Early identification of micrometastasis could allow the selective and timely inclusion of high risk patients in more aggressive treatment and follow-up protocols, with potential survival benefits. At the same time SLNB could spare node-negative patients the morbidity of potentially unnecessary additional therapy. The aim of our study is to introduce the concept of SLNB for patients with high risk cutaneous SCC, by reporting on a case series of high risk cutaneous SCC undergoing SLNB at our hospital and performing a critical review and pooled analysis of all published cases of SLNB for cutaneous SCC. Patients and methods Case series A total of 22 patients with high risk cutaneous SCC, clinically node-negative, underwent SLNB, between 1998 and 2005, at the Plastic Surgery Department of the Istituto Dermopatico dell’Immacolata (IDI), a large dermatological hospital in Italy. The mean age of patients was 64.2 years (standard deviation (SD) 13.8; range: 35e80 years) and 86.4% were men. Patients were identified as having high metastatic risk, if presenting any of the risk criteria reported in the literature.1,5 In particular, 14 patients had lesions > 2 cm in diameter, 12 patients had SCCs infiltrating the subcutis, bone or muscles, 10 SCCs were >4 mm in depth, 15 SCCs were located at high risk sites, such as lower lip or lip commissure (n ¼ 13) and ear (n ¼ 2), 10 patients had poorly or moderately differentiated SCCs, two SCCs showed perineural infiltration and three patients had recurrent tumors. No patient was immunosuppressed. Among included patients, 73% (n ¼ 16) responded to three or more high risk criteria. Mean tumor size was 2.7 cm (median: 2.4 cm; range: 1.0e6.7 cm). Patients with genital SCC and clinical signs of metastasis were excluded. Follow-up visits and lymph node ultrasound examinations were scheduled every six months during the first two years after surgery and once a year thereafter. When patients could not be visited at our hospital, follow-up
365
information was obtained from medical records and telephone interviews. The study was approved by the institutional ethical committee and written informed consent was obtained from participating patients. Lymphoscintigraphy was performed after injecting 30e50 MBq of Technetium-99m radiolabelled nanocolloid at the site of the tumor. Static and dynamic acquisition was started immediately after the injection and the skin projection of the sentinel lymph node (SLN) was marked with ink. After 3e18 h, surgical removal of the primary tumor and SLNB were performed at the plastic surgery department, using a handheld gamma camera for the detection of the SLN. The primary lesion was excised first, before performing the SLNB, in order to prevent ‘‘shine-through’’. Radiolocalization was combined with intradermal injection of vital blue dye at the primary tumor site at the beginning of the surgical procedure. For head and neck tumors blue dye was not used, because, in our experience, for this location it is less effective, probably due to the rapid lymphatic wash-out, and it can cause permanent facial tattooing.19 Using these techniques on melanoma patients, our SLN detection rate is 97.4%,20 which is in agreement with the literature.21 The sentinel node radiolocalization technique, applied to the first patients with cutaneous SCC treated at our hospital, was previously described.19,22 The present study, examining the histologic and clinical characteristics associated with SLN positivity, includes the complete series of patients with high risk cutaneous SCC recruited at our hospital. Surgical excision of the primary tumors has been performed removing wide margins, with tissue margins examined histologically, following international guidelines.8 SLNs were sectioned at 3 mm intervals and included in paraffin. Ten 5-mm sections were then obtained and examined using hematoxylineeosin and immunohistochemical staining with anticytokeratin antibodies (MNF116 DAKO). Literature review and pooled analysis We carried out a review of the literature on SLNB for cutaneous SCC. The Medline, Ovid and Cochrane Library databases were searched using the following terms: sentinel lymph node, squamous cell carcinoma, cutaneous, skin, lip; accepted publication languages were English, French, German, Italian and Spanish. We contacted the authors of the studies asking for additional information on clinical and histopathological characteristics of included cases, but no further data were obtained. Cases of SLNB for cutaneous SCC were tabulated and a pooled analysis, including also our new cases, was performed. ManteleHaenszel Odds Ratios (OR) and 95% Confidence Intervals (95% CI) were calculated for the association between tumor size (categorized in 2 cm, 2.1e3 cm and >3 cm) and positive SLN.
366
C. Renzi et al. / EJSO 33 (2007) 364e369
Moreover, multiple logistic regression was used for examining the independent effect on the likelihood of SLN metastases of tumor size and of perineural, vascular, bone, cartilage or muscle infiltration, controlling for patient age. Because detailed information on infiltration was not consistently reported for sufficient numbers of patients, in order to avoid excessively sparse data, a summary variable was created, i.e. infiltration of any of the previously mentioned structures versus no infiltration. We used the computer package STATA-9.0 for Windows for statistical analyses. Results Case series Among the 22 patients treated at IDI, lymphoscintigraphy identified 41 SLNs (median: 1.8 nodes per patient; range: 1e4). SLNB was performed under general anesthesia in nine patients and with local anesthesia with mild intravenous sedation in 13 patients. Patients were discharged within the second day after surgery. We observed two minor complications, i.e. two cases of dehiscence of the surgical wound in tumors of the lip, not requiring further surgical procedures. We did not observe any other complications. Of the 41 SLNs examined by means of immunostaining, one positive node was found among a 70-year-old man, with an SCC of the left foot (fifth toe). The ulcerated tumor had a diameter of 2.5 cm and at histopathology it was poorly differentiated, it showed vascular, perineural and bone infiltration and tumor depth was >4 mm. The positive lymph node was detected in the left inguinal basin. At radical lymph node dissection of the involved basin one node was positive for metastasis from SCC. Four months after the initial surgery, the SCC had infiltrated the left foot, at the base of the amputated toe, and showed in-transit metastasis on the thigh. Moreover, lymph node metastases were noted in the contralateral inguinal basin at ultrasound and were confirmed by histological examination. Subsequently the patient started chemotherapy. Clinical and ultrasound examinations performed before surgery in this patient had not shown any enlarged lymph nodes nor any signs of potential metastases. Overall, the median follow-up was 17 months (range: 6e64 months). Of the 21 patients with no evidence of micrometastases at SLNB, 17 are still alive, without clinical signs of tumor spread. One patient had a local recurrence. Four patients died during follow-up, between 76 and 82 years of age, due to causes not related to the SCC (e.g. stroke, lung cancer, etc.). Literature review and pooled analysis We identified 11 papers reporting SLNB for cutaneous SCC.13e17,23e28 Six of them 23e28 are reports of single
cases. Two studies14,15 included also some patients with genital or perineal SCCs. These patients were excluded from our analyses. Summary information on the studies and characteristics of patients with positive SLNs are reported in Table 1. The biggest study included 20 patients with SCC of the lower lip,16 but SLN were identified only on 18 of them. Proportions of positive SLNs in the literature range between 12.5% and 44.4%. Pooling together patients from all published studies and from our case series (total 83 patients) showed that the greatest number of SLN biopsies was performed on SCCs of the lower lip (n ¼ 36), followed by SCCs of the face (excluding lip and ear) (n ¼ 10) and SCCs of the leg (excluding foot) (n ¼ 10). Among patients with a tumor at the lower lip, face and leg, positive SLNs were found in 8.3% (n ¼ 3), 30% (n ¼ 3) and 20% (n ¼ 2), respectively. Overall, among the 83 patients, 16.9% (n ¼ 14) had positive SLNs (95% CI: 9.5e26.7). All patients with positive SLNs had lesions > 2 cm in diameter (Table 1). Among patients with tumors 2 cm, 2.1e3 cm and >3 cm in diameter, proportions of positive SLNs were 0%, 15.8% and 30.4%, respectively (Fisher’s exact, p ¼ 0.058). An increase in tumor size from 2 cm to 2.1e3 cm to >3 cm was associated with a 2.8-fold higher odds of finding positive SLN (ManteleHaenszel OR ¼ 2.76; 95% CI 1.2e6.5; p ¼ 0.02). Furthermore, multiple logistic regression has shown that tumor size is significantly associated with a higher likelihood of positive SLNs (OR ¼ 4.27; 95% CI 1.2e15.3; p ¼ 0.026), independently of vascular, perineural, bone or muscle infiltration and of patient age. Infiltration and age showed no significant association with SLN status. Discussion Our case series and review of the literature have shown that SLNB has recently started to be used in selected cases of high risk cutaneous SCC, and our results support the concept that it can be applied for staging of high risk cutaneous SCC. However, our report also highlights the need of rigorous prospective multicentre studies, before being able to draw any conclusions. In fact, published studies on SLNB for cutaneous SCC and our present case series are all based on limited numbers of patients and short follow-up times. The small sample size can lead to marked differences in the results, simply due to sampling variation. This might partially explain the discordance between the relatively high proportions of positive SLNs for cutaneous SCCs reported in the literature,13e17 compared to our case series. Furthermore, our review is limited by the lack of uniform criteria for defining high risk patients. This reflects the fact that evidence is lacking particularly regarding the risks associated with the simultaneous presence of multiple
C. Renzi et al. / EJSO 33 (2007) 364e369
367
Table 1 Positive sentinel lymph node (SLN) biopsies for cutaneous SCC reported in the literature and characteristics of patients with positive sentinel nodes Study
No. of SLNþ pts/total pts studied (%)
Age of SLNþ pts
Tumor location of SLNþ pts
Tumor size of SLNþ pts (cm)
Tumor depth of SLNþ pts
Michl, 2003
2/9 (22.2)
52 78
Presternal Lower leg
9.0 5.0
Reschly, 2003
4/9 (44.4)
73 66 41 45
Wrist Lower leg Clavicle Scalp
4.5 11.0 3.0 3.5
>4 mm >4 mm >4 mm >4 mm
Nouri, 2004
1/8 (12.5)
n.a.
Face
n.a.
n.a.
Wagner, 2004
2/11 (18.2)
66 93
Face Face
Altinyollar, 2002
3/18 (16.6)
n.a. n.a. n.a.
Lower lip Lower lip Lower lip
Stadelmann, 1997 Weisberg, 2000 Perez-Naranjo, 2005 Ardabili, 2003 Yamada, 2004 Ozcelik, 2004
1/1 0/1 0/1 0/1 0/1 0/1
72
Renzia
1/22 (4.5)
70
Subcutis Deep dermis
4.5 3.0
n.a. n.a.
>2.0 >2.0 >2.0
n.a. n.a. n.a.
Wrist
4.0
n.a.
Foot
2.5
>4 mm
SLN ¼ sentinel lymph node; pts ¼ patients; and n.a. ¼ not available. a IDI case series.
risk factors. Unfortunately, no study until now has had sufficient power to examine, in multivariate analysis, the independent effect of each factor (and interaction between factors) on the risk of recurrence and metastasis. For example, tumor size has been shown to be an important risk factor for metastasis, but different definitions and cut-offs have been used: a commonly used cut-off size is >2 cm,1,8 whereas the National Comprehensive Cancer Network (NCCN) guidelines29 group together tumor size and location as one risk factor, with size being divided into three categories such as 6 mm, 10 mm, 20 mm, depending on tumor location. Among the reviewed studies, somewhat different cutoffs regarding tumor size were used for identifying high risk patients: one study15 included SCCs > 1 cm, if located on face and distal extremities, or >4 cm for trunk and proximal extremities; other studies13,17 included SCCs > 2 cm for all locations (except lip or ear, that were considered high risk independently of size); other authors included only SCCs 4 cm.14 It should be highlighted, that the majority of included patients presented also other high risk factors, in addition to size and location, e.g. infiltration of the deep dermis, subcutis, muscles or bone, poor differentiation, etc. Similarly, in our case series, more than 70% of patients responded to three or more high risk criteria. Considering the uncertainty on the best definition for high risk patients and the still preliminary data on SLNB for cutaneous SCC, a conservative approach for future
studies could be, for example, including patients with at least two or three high risk factors. The pooled analysis has shown that an increase in tumor size from 2 cm to 2.1e3 cm to >3 cm is associated with a ManteleHaenszel OR of 2.8 of finding lymph node micrometastasis. This is in agreement with studies on clinically evident metastases, reporting a three times higher metastatic risk for tumors > 2 cm compared to smaller tumors.5 It is, however, noteworthy, that recent studies on head and neck cutaneous SCCs18 have shown that also relatively small lesions (<2 cm) are at risk of lymph node metastasis, particularly if thickness is 4 mm. This suggests that size alone is probably a weak independent predictor of metastases and other factors, particularly thickness, should also be considered.18,30 Our study, including both head and neck and non-head and neck SCCs, had limited power for examining the effect of other risk factors, such as depth of infiltration, perineural or vascular infiltration and specific tumor locations. Previous studies have shown that most metastatic lymph nodes from head and neck cutaneous SCCs occur in the parotid gland.18 Unfortunately, in our series, SCCs located on or around the external ear and the frontotemporal scalp, which can metastatize to lymph nodes within the parotid, with or without involvement of cervical nodes,18 are underrepresented. In our series, the majority of patients had SCCs of the lip or lip commissure. Despite being usually considered high risk, none showed positive SLNs. The small number of patients in our series with lesions located near the
368
C. Renzi et al. / EJSO 33 (2007) 364e369
parotid and the fact that some important risk factors, such as recurrent SCCs or immunosuppression, were underrepresented, limits the generalizability of our results and might partially explain the lower than expected SLN positivity. Further studies, looking specifically at cutaneous SCCs with high risk characteristics located in the parotid drainage area, might show higher incidence of positive SLNs. Large, multicenter studies with at least five-year followup are needed for examining the independent effect of specific risk factors on the probability of positive SLNs by means of multivariate analysis and for evaluating the role and cost-effectiveness of sentinel lymph node biopsy for high risk cutaneous SCC.21 It has been suggested that SLNB might have a greater potential of controlling metastatic dissemination among patients with cutaneous SCC compared to melanoma patients, because SCCs tend to metastasis mainly to regional lymph nodes and because of their radiosensitivity.13 In any case, all patients with high risk SCC should be followed-up closely. Studies have shown that the majority of recurrences and metastases take place within two years after treatment, with 95% of recurrences and metastases being observed within five years. Thus, close follow-up is essential during this period of time to detect recurrences, metastases and also new primary skin cancers.1,4,29 High risk individuals should undergo screening once or twice yearly and, whenever possible, patients should be instructed in self-examination and use of sunscreens.1,8 In conclusion, our report supports the concept that SLNB can be applied for high risk cutaneous SCC. Large, multicenter, longitudinal studies are needed to further evaluate clinical and histopathological characteristics associated with positive SLNs and the cost-effectiveness of SLNB in patients with high risk cutaneous SCC. These studies could be particularly valuable, considering the increasing incidence of cutaneous SCC.
Acknowledgements We would like to thank N. Melo Salcedo and S. Bolli for assisting in the data collection and data entry. The study was financially supported by the Italian Ministry of Health. The authors have no conflict of interest to disclose.
References 1. Alam M, Ratner D. Cutaneous squamous cell carcinoma. N Engl J Med 2001;344:975–83. 2. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK. Trends in the population based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992. Arch Dermatol 1997;133:735–50. 3. Rudoph R, Zelac D. Squamous cell carcinoma of the skin. Plast Reconstr Surg 2004;114:82–94.
4. Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 2002;28: 268–73. 5. Rowe D, Carroll R, Day C. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 1992;26:976–90. 6. Fernandez-Angel I, Rodriguez-Archilla A, Aneiros Cachaza J, Munoz Medina M, Serrano Ortega S. Markers of metastasis in lip cancer. Eur J Dermatol 2003;13:276–9. 7. Schwartz RA, Stoll HL. Squamous cell carcinoma. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. 4th ed., Dermatology in general medicine, vol. 1 New York: McGraw-Hill; 1993, p. 821–39. 8. Motley R, Kersey P, Lawrence C. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Plast Surg 2003;56:85–91. 9. Kell MR, Kerin MJ. Sentinel lymph node biopsy. BMJ 2004;328: 1330–1. 10. Berk DR, Johnson DL, Uzieblo A, Kiernan M, Swetter SM. Sentinel lymph node biopsy for cutaneous melanoma. Arch Dermatol 2005; 141:1016–22. 11. McMasters KM, Noyes RD, Reintgen DS, et al. Lessons learned from the sunbelt melanoma trial. J Surg Oncol 2004;86:212–23. 12. Morton DL. Interim results of the multicenter selective lymphadenectomy trial (MSLT-I) in clinical stage I melanoma. In: Presented at the American Society of Clinical Oncology, Orlando, FLA; May 14, 2005. Available at: http://www.asco.org. 13. Reschly MJ, Messina J, Zaulyanov L, Cruse W, Fenske N. Utility of sentinel lymphadenectomy in the management of patients with highrisk cutaneous squamous cell carcinoma. Dermatol Surg 2003;29: 135–40. 14. Wagner JD, Evdokimow DZ, Weisberger E, et al. Sentinel node biopsy for high-risk nonmelanoma cutaneous malignancy. Arch Dermatol 2004;140:75–9. 15. Michl C, Starz H, Bachter D, Balda B-R. Clinical and laboratory investigations Sentinel lymphonodectomy in nonmelanoma skin malignancies. Br J Dermatol 2003;149:763–9. 16. Altinyollar H, Berberoglu U, Celen O. Lymphatic mapping and sentinel lymph node biopsy in squamous cell carcinoma of the lower lip. Eur J Surg Oncol 2002;28:72–4. 17. Nouri K, Rivas MP, Pedroso F, Bhatia R, Civantos F. Sentinel Lymph node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck. Arch Dermatol 2004;140:1284. 18. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck. Cancer 2006;106:2389–96. 19. Tartaglione G, Potenza C, Caggiati A, et al. Lymphatic mapping and sentinel node identification in squamous cell carcinoma and melanoma of the head and neck. Tumori 2002;88:S39–41. 20. Caggiati A, Migliano E, Potenza C, et al. Sentinel node biopsy for malignant melanoma. Technical details and clinical results on 390 patients. Minerva Chir 2002;57:481–7. 21. Swan MC, Furniss D, Cassell OC. Surgical management of metastatic inguinal lymphadenopathy. BMJ 2004;329:1272–6. 22. Tartaglione G, Potenza C, Caggiati A, Gabrielli F, Russo A, Pagan M. Sentinel node radiolocalisation and predicative value in lip squamous cell carcinoma. Radiol Med 2003;106:256–61. 23. Stadelmann WK, Javaheri S, Cruse CW, Reintgen DS. The use of selective lymphadenectomy in squamous cell carcinoma of the wrist: a case report. J Hand Surg 1997;22:726–31. 24. Weisberg NK, Bertagnolli MM, Becker DS. Combined sentinel lymphadenectomy and Mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2000;43(3): 483–8. 25. Perez-Naranjo L, Herrera-Saval A, Garcia-Bravo B, Perez-Bernal AM, Camacho F. Sentinel lymph node biopsy in recessive dystrophic epidermolysis bullosa and squamous cell carcinoma. Arch Dermatol 2005;141:110–1.
C. Renzi et al. / EJSO 33 (2007) 364e369 26. Ardabili M, Gambichler T, Rotterdam S, Altmeyer P, Hoffmann K, Stucker M. Metastatic cutaneous squamous cell carcinoma arising from a previous area of chronic hypertrophic lichen planus. Dermatol Online J 2003;9:10. 27. Yamada M, Hatta N, Sogo K, Komura K, Hamaguchi Y, Takehara K. Management of squamous cell carcinoma in a patient with recessivetype epidermolysis bullosa dystrophica. Dermatol Surg 2004;30: 1424–9.
369
28. Ozcelik D, Tatlidede S, Hacikerim S, Ugurlu K, Atay M. The use of sentinel lymph node biopsy in squamous cell carcinoma of the foot: a case report. J Foot Ankle Surg 2004;43:60–3. 29. Miller SJ. The National comprehensive cancer network (NCCN) guidelines of care for nonmelanoma skin cancers. Dermatol Surg 2000;26:289–92. 30. Veness MJ. Defining patients with high-risk cutaneous squamous cell carcinoma. Australas J Dermatol 2006;47:28–33.