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Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5-year follow-up
Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5-year follow-up Igal Leibovitch, MD,a Shyamala C. Huilgol, FACD,b,c Dinesh Selva, FRANZCO,a,d Shawn Richards, FACD,e and Robert Paver, FACDe Adelaide, South Australia, and Sydney, New South Wales, Australia Background: Long-term follow-up is essential to evaluate the role of Mohs micrographic surgery (MMS) in the treatment for cutaneous basal cell carcinoma (BCC). Objective: Our purpose was to report the 5-year follow-up outcome of patients treated with MMS for BCC. Method: This prospective, multicenter case series included all patients in Australia treated with MMS for BCC, who were monitored by the Skin and Cancer Foundation between 1993 and 2002. Parameters recorded were patient demographics, duration of tumor, site, preoperative tumor size, recurrences before MMS, histologic classification of malignancy, postoperative defect size, and 5-year recurrence after MMS. Results: Three thousand three hundred seventy (3370) patients (1594 female and 1776 male patients) completed a 5-year follow-up period. Fifty-six percent of the tumors were primary and 44% were previously recurrent. Most of them (98.4%) were located on the head and neck, and the most common histologic subtypes were nodulocystic (29.3%) and infiltrating (28.3%). Recurrence at 5 years was diagnosed in 1.4% of primary and in 4% of recurrent tumors. Previous tumor recurrence (P \ .001), longer tumor duration before MMS (P = .015), infiltrating histology (P = .13), and more levels for tumor (P \ .001) were the main predictors for tumor recurrence after MMS. Limitation: Data were missing for some outcome measures. Conclusion: The low 5-year recurrence rate of BCC with MMS emphasizes the importance of margincontrolled excision. ( J Am Acad Dermatol 2005;53:452-7.)
A
variety of surgical and nonsurgical treatment modalities achieve successful results in treating basal cell carcinoma (BCC). These include curettage and cautery, surgical excision, cryotherapy, radiation therapy, photodynamic therapy (PDT), topical 5-fluorouracil (5-FU), and topical imiquimod.1-4
From the Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences,a and the Department of Dermatology,b Royal Adelaide Hospital, University of Adelaide; Wakefield Clinic, Adelaidec; the Departments of Surgery and Medicine, University of Adelaided; and Skin and Cancer Foundation Australia, Sydney.e Funding sources: None. Conflict of interest: None identified. Reprints not available from the authors. Correspondence to: Dr Shyamala Huilgol, Wakefield Clinic, 270 Wakefield St, Adelaide, SA, 5000. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.087
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It is known that recurrence rates are higher for larger and previously recurrent tumors, as well as for more aggressive histologic subtypes.3-7 Standard excision has a 5-year recurrence rate of 3.2% to 10% for primary tumors, and more than 17% for recurrent BCC.3,5-7 Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation; hence it is widely used for high-risk tumors (recurrent or incompletely excised tumors, mid-facial location, [2 cm, aggressive histology, deep extension, and PNI).1,4 Reported recurrence rates with MMS are 1% to 3% for primary tumors and 5% to 7% for recurrent tumors.2,6,7 These figures are based on retrospective data and a limited number of large-scale, prospective studies.2,8,9 The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia with the aim of collecting data prospectively and involved all Mohs surgeons in the country. This article reports the outcome of patients with BCC who completed a 5-year follow-up period.
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METHOD We conducted a prospective, noncomparative, multicenter, interventional case series of patients with cutaneous BCC treated with MMS in Australia and monitored by the Skin and Cancer Foundation Australia between 1993 and 2002. All patients were treated by fellowship-trained Mohs surgeons using standard fresh-frozen MMS techniques. The general technique was based on constructing a tissue map followed by color coding of the excised tissue. Frozen sections of the entire outer margin in a continuous layer were prepared, and the tissue was stained with hematoxylin and eosin. A trained Mohs technician performed all frozen-section preparation. Residual tumor was mapped, and serial levels were excised until the surgical margins were cleared of tumor. All resections, mapping, and tissue examination were carried out by the Mohs surgeons. The decision whether to perform initial curettage for tumor debulking was made by the individual surgeons, and this was not counted as a first level of excision. In addition, surgical margin sizes for initial and subsequent layers also varied between different surgeons. The criteria for selection were all cases with BCC diagnosed histologically and treated with MMS. The following parameters were recorded: patient identification number, age, sex, reason for referral, duration of tumor, site, recurrences before MMS, preoperative tumor size, histologic classification of malignancy, evidence of perineural invasion (PNI), and postoperative defect size. Tumor and postoperative defect size were defined into 8 groups based on the maximum diameter using a straight ruler: 0-0.9 cm, 1-1.9 cm, 2-2.9 cm, 3-3.9 cm, 4-4.9 cm, 5-5.9 cm, 6-7.9 cm, 8-10 cm, and [10 cm. Subclinical extension of the tumor was calculated as the difference in number of size groups between the defect and tumor size. The primary outcome measure was BCC recurrence at 5-year follow-up for patients undergoing MMS between 1993 and 1999.
Statistical analysis Associations between categorical variables were analyzed by means of x2 tests, with the MantelHaenszel test for linear association used where appropriate. Fisher’s exact test was used if expected values were less than 5. Comparison of normally distributed variables among groups was performed by using t tests and analysis of variance; their nonparametric equivalent was used for non-normally distributed data. Exact 95% confidence intervals (CIs) were calculated for the 5-year recurrence rates.
Analyses were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS Patients with 5-year follow-up Three thousand three hundred seventy (3370) patients (1594 female and 1776 male patients) completed a 5-year follow-up period after MMS. The mean age (6 standard error of the mean) of these patients was 61 6 14 years (median, 62; range, 17-92 years). In 1886 patients (56.0%) the lesion was a primary tumor, and in 1484 patients (44.0%) the lesion was a recurrent tumor (previously treated with non-Mohs procedures). The most common stated reasons for patient referral for MMS in patients with 5-year follow-up were tumor recurrence (35.8%), tumor site (24.5%), and a poorly defined tumor (20.9%). In most patients (1732 patients, 51.4%) the tumor age before excision ranged between 1 and 5 years, and in 28.2% it was less than 1 year. Most of the tumors were located on the head and neck (98.4%). The most common anatomic site was the nose (1295 patients, 38.4%), followed by the cheek and maxilla (577 patients, 17.1%), auricular region (369 patients, 10.9%), and periocular area (366 patients, 10.9%). Tumor size was less than 2 cm in 2579 patients (76.5%), less than 1 cm in 1089 patients, and between 1.0 and 1.9 cm in 1492 patients. The postexcision defect size was less than 2 cm in 1448 patients (43.0%), whereas in the majority of patients (57.0%) it was larger than 2 cm. The percentage of patients with significant subclinical extension (defined as tumor defect exceeding tumor size by at least two size groups) was 22.1%. The most common histologic subtypes of BCC were nodulocystic (986 patients, 29.3%), infiltrating (955 patients, 28.3%), and superficial (443 patients, 13.1%). PNI was diagnosed in 76 patients who completed a 5-year follow-up period, and these data are presented in part 3 of this study. Five-year follow-up data were not available for 7757 patients. We compared the parameters of these patients with those who have 5-year follow-up data to identify differences between the two groups (Table I). Patients with no follow-up data at 5 years were less likely to have tumors on the nose (P = .08) and nodulocystic histology (P = .04). No significant differences were noted in all other parameters compared. Recurrence at 5-year follow-up Recurrence at 5-year follow-up after MMS was diagnosed in 86 of the 3370 patients (2.6%; exact 95%
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Table I. Clinical characteristics of patients with and without a 5-year follow-up period after Mohs micrographic surgery for basal cell carcinoma
Clinical feature
Male/female ratio Age, y (mean 6 SEM) Previously recurrent tumors Tumor age (1-5 y) Most common tumor sites
Patients with 5-y follow-up (N = 3370)
Patients without 5-y follow-up (N = 7757)
1.11 61 6 14
1.13 62 6 14
44.0%
43.7%
51.4% Nose (38.4%) Cheek and maxilla (17.1%) Auricular area (10.9%) Periocular region (10.3%) Tumor size \2 cm 76.5% Defect size [2 cm 57.0% Nodulocystic Most common (29.3%) histologic subtypes Infiltrating (28.3%) Superficial (13.1%)
56.7% Nose (27.6%)* Cheek and maxilla (16.3%) Auricular area (11.6%) Periocular region (13.6%) 73.4% 53.5% Nodulocystic (22.0%)y Infiltrating (31.7%) Superficial (13.8%)
SEM, Standard error of the mean. *P = .08. y P = .04.
CI, 0.02-0.031). There were 26 cases of recurrence at 5 years in the 1886 patients with primary BCC (1.4%; exact 95% CI, 0.09-0.02), and there were 60 cases of recurrence in the 1484 patients with previously recurrent BCC (4.0%; exact 95% CI, 0.031-0.052) (P\ .001 for difference in recurrence rates between primary and previously recurrent tumors). The 86 patients with recurrence at 5 years included 50 male patients (58.1%) and 36 female patients (41.9%) (P = .3). Most of these patients (52 cases, 60%) were sent for MMS with previous recurrence as the stated reason for referral. Tumor age before MMS in relation to recurrence at 5 years is presented in Table II. Recurrence at 5 years was associated with a longer tumor duration before excision (P = .015). The most common site for recurrence was the nose (38.4% of cases), followed by the cheek and maxilla (17.1%) and auricular area (10.9%) (Table III). These were also the most common sites for BCC treated by MMS, as well as for all patients with 5-year follow-up. Therefore no statistically significant association between tumor site and recurrence was found.
Table II. Tumor age before excision in patients with 5-year follow-up after Mohs micrographic surgery for basal cell carcinoma
Tumor age* (y)
\1 1-5 5-10 >10 Data not available
No recurrence at 5 y (N = 3284)
934 1683 292 110 265
(28.4%) (51.2%) (8.9%) (3.3%) (8.1%)
Recurrence at 5 y (N = 86)
16 49 15 3 3
(18.6%) (57.0%) (17.4%) (3.5%) (3.5%)
Overall cases with 5-year follow-up (N = 3370)
950 1732 307 113 268
(28.2%) (51.4%) (9.1%) (3.3%) (7.9%)
*P \ .015.
Tumor size before MMS was less than 2 cm in 66 of the patients (76.7%) with recurrence at 5 years, and in 2525 (76.6%) of the patients with no recurrence at 5 years (Table IV). No association was found between tumor size at presentation and recurrence at 5 years (P = .90). The postexcision defect size was less than 3 cm in 60 (70.0%) of the patients with recurrence at 5 years, and in 2361 (71.9%) of the patients with no recurrence at 5 years (Table V). No association was found between postexcision defect size and recurrence at 5 years (P = .17), as well as between subclinical extension and recurrence at 5 years (P = .33). The most common histologic subtypes of BCC in patients with recurrence at 5 years were infiltrating (37.2%), nodulocystic (17.4%), and superficial (13.9%) (Table VI). The infiltrating subtype appeared to be associated with recurrence at 5 years; however, this was not statistically significant (P = .13). PNI was diagnosed in 6 patients with 5-year recurrence, and the data are presented in part 3 of this study. The mean number of levels required for complete tumor excision in patients with recurrence at 5 years was 2.11 (median, 2.0; range, 1-6 levels), whereas in patients with no recurrence at 5 years it was 1.72 (median, 2.0; range 1-8 levels) (P \.001).
DISCUSSION The increase in the worldwide incidence of BCC has resulted in many studies that have evaluated different surgical and nonsurgical treatment modalities.2,3 The choice of treatment options is based on multiple variables, such as patient factors (age, sex, general health), tumor characteristics (size, location, histologic subtype), as well as the treating physician’s preference and available resources.2,3 Nonsurgical treatments commonly used for BCC include cryotherapy, radiation therapy, and topical agents (5-FU, imiquimod and PDT). Cryotherapy using liquid nitrogen was reported to achieve cure
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Table III. Sites of basal cell carcinoma in relation to 5-year recurrence in patients treated with Mohs micrographic surgery No recurrence at 5 y (N = 3284)
Site of BCC
Scalp Forehead Periocular area Auricular area Cheek and maxilla Nose Lips Chin and mandible Neck Upper limbs Trunk Genitalia Lower limbs Data not available
63 348 359 356 562
Recurrence at 5 y (N = 86)
(1.9%) (10.6%) (10.9%) (10.8%) (17.1%)
3 5 7 13 15
1260 (38.4%) 123 (3.7%) 55 (1.7%) 89 14 35 2 3 15
(3.5%) (5.8%) (8.1%) (15.1%) (17.4%)
Overall cases with 5-y follow-up (N = 3370)
66 353 366 369 577
(2.0%) (10.5%) (10.9%) (10.9%) (17.1%)
35 (40.7%) 1295 (38.4%) 3 (3.5%) 126 (3.7%) 1 (1.1%) 56 (1.7%)
(2.7%) (0.4%) (1.0%) (0.06%) (0.09%) (0.5%)
1 (1.1%) 0 2 (2.3%) 0 0 1 (1.1%)
90 14 37 2 3 16
(2.7%) (0.4%) (1.1%) (0.06%) (0.09%) (0.5%)
Table IV. Preoperative tumor sizes in relation to recurrence at 5 years in patients treated with Mohs micrographic surgery for basal cell carcinoma Tumor size* (cm)
Overall cases No recurrence Recurrence at with 5-y follow-up at 5 y (N = 3284) 5 y (N = 86) (N = 3370)
\1 1063 (32.4%) 1-1.9 1452 (44.2%) 2-2.9 445 (13.5%) 3-3.9 159 (4.8%) 4-4.9 60 (1.8%) 5-5.9 34 (1.0%) 6-7.9 8 (0.2%) 8-10 4 (0.1%) Data not 59 (1.8%) available
26 40 11 6
(30.2%) (46.5%) (12.8%) (7.0%) 0 1 (1.2%) 0 0 2 (2.3%)
1089 1492 456 165 60 35 8 4 61
(32.3%) (44.3%) (13.5%) (4.9%) (1.8%) (1.0%) (0.2%) (0.1%) (1.8%)
*P = .9.
rated as high as 99%, but these series excluded highrisk tumors such as recurrent, large, and midfacial BCCs with aggressive histologic features, which are generally accepted as a relative contraindication for treatment with cryotherapy.1-4 Radiation therapy is considered a very useful mode of treatment, especially in older and disabled patients with large tumors, when surgical treatment may not be appropriate. The estimated 5-year recurrence rate is 7.4% to 8.7% for primary BCC and 9.5% to 9.8% for recurrent tumors.6,7,10 In a recent report by Kwan, Wilson, and Moravan,11 the 4-year recurrence rate for locally advanced BCC was 14%, whereas
Table V. Postoperative defect sizes in relation to recurrence at 5 years in patients treated with Mohs micrographic surgery for basal cell carcinoma
Defect size* (cm)
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 >10 Data not available
No recurrence at 5 y (N = 3284)
111 1310 940 472 181 107 88 20 10 45
(3.4%) (39.9%) (28.6%) (14.4%) (5.5%) (3.3%) (2.7%) (0.6%) (0.3%) (1.4%)
Recurrence at 5 y (N = 86)
4 23 33 10 7 5 3
(4.6%) (26.7%) (38.4%) (11.6%) (8.1%) (5.8%) (3.5%) 0 0 1 (1.2%)
Overall cases with 5-y follow-up (N = 3370)
115 1333 973 482 188 112 91 20 10 46
(3.4%) (39.6%) (28.9%) (14.3%) (5.6%) (3.3%) (2.7%) (0.6%) (0.3%) (1.4%)
*P = .17.
Table VI. Histologic subtypes of basal cell carcinoma in relation to recurrence at 5 years in patients treated with Mohs micrographic surgery
Histologic subtype
Nodulocystic Infiltrating* Superficial Morpheic Micronodular Basosquamous Combined subtypes Data not available
No recurrence Recurrence at 5 y (N = 3284) at 5 y (N = 86)
971 923 431 246 138 94 37
(29.6%) (28.1%) (13.1%) (7.5%) (4.2%) (2.9%) (1.1%)
444 (13.5%)
15 32 12 10 3 4 2
(17.4%) (37.2%) (13.9%) (11.6%) (3.5%) (4.7%) (2.3%)
8 (9.3%)
Overall cases with 5-y follow-up (N = 3370)
986 955 443 256 141 98 39
(29.3%) (28.3%) (13.1%) (7.6%) (4.2%) (2.9%) (1.2%)
452 (13.4%)
*P = .13.
Zagrodnik et al12 reported an estimated 5-year recurrence rate of 8.2% for nodular BCC and 26.1% to 27.7% for superficial and sclerosing BCC. The main disadvantage of this treatment is the lack of tumor margin control and the potential side effect, especially in the periocular region (cataract, dry eye, and lacrimal duct obstruction).1,4 Topical 5-FU is useful for low-risk and nonfacial BCC and is generally used for treating multiple superficial BCCs on the trunk and lower extremities.1,13 Imiquimod 5% is a new immune-modulating drug that stimulates monocytes and dendritic cells to produce interferon alfa and other cytokines. Recent publications demonstrate efficacy of this drug in short-term clearance of superficial BCC,14-17 but long-term recurrence rates have not yet been
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Table VII. Comparative clinical and 5-year recurrence data on Mohs micrographic surgery for basal cell carcinoma Mohs25,26
Study years Tumor location Overall No. of tumors with 5-y follow-up (primary/secondary) Overall 5-y recurrence (primary/secondary)
Robins27
Julian and Bowers28
Current study
NA Head 8643 (7257/1386)
1965-1980 Head 2960 (NA)
1981-1995 Head 228 (NA)
1993-2002 Mainly head and neck 3370 (1886/ 1484)
1.0% (0.7%/3.2%)
2.6% (1.8%/3.4%)
3.8% (1.7%/4.8%)
2.6% (1.4%/ 4.0%)
NA, Not available.
assessed. Topical PDT is based on application of the porphyrin aminolevulinic acid to the tumor, which is absorbed and makes the lesion photosensitive. Photodestruction is achieved with exposure to light with a wavelength of 620 to 670 nm.3 An important determinant of response to treatment is tumor thickness; Aminolevulinic acidePDT was shown to be effective in treating superficial BCC, with short-term clearance rates of 87% to 100%, whereas nodular BCC had lower rates of 10% to 70% and required prior debulking to enhance the response to treatment.18-21 Morpheic and pigmented lesions seem to respond poorly to PDT.20 There are no 5-year follow-up data, but short-term results for superficial BCC are encouraging.22 Surgical excision is the most frequent treatment modality for BCC. Excision of BCC without margin control is estimated to result in a 5-year recurrence rate of 3.2% to 10.0% for primary tumors and more than 17% for recurrent BCC.3,5-7 In a review of 2606 patients with primary BCC treated with surgical excision and followed up for 5 years, Rowe, Carroll, and Day6 calculated a 5-year recurrence rate of 10.1%, whereas in 522 patients with previously recurrent tumors the recurrence rate was 17.4%. Standard histologic assessment of excision specimens with breadloaf sectioning examines only 0.2% of the margins. In contrast, MMS utilizes en-face sections of the entire outer surface of the excised tissue, thereby examining close to 100% of the peripheral and deep margins.3,23,24 It is generally accepted that MMS is indicated in the treatment of high-risk tumors; these are usually tumors with risk factors such as previous recurrence, midfacial location (periocular area, nose, and lips), size larger than 2 cm, or aggressive histology (morpheic, infiltrative, basosquamous, or micronodular). Additional factors include deep invasion, PNI, incompletely excised tumors, and clinically indistinct borders.1,3 A limited number of large-scale or prospective studies were conducted previously to evaluate the
role of MMS in treating BCC (Table VII). Our study, which is based on the Australian MMS database, is the largest reported prospective nationwide series of patients with BCC managed by MMS and followed up for 5 years. Our series is characterized by a high percentage of large head and neck, as well as recurrent, tumors, which are considered more aggressive and are classified as high-risk tumors.1 The 5-year recurrence rate in primary cases was 1.4%, whereas in previously recurrent cases it was 4.0%. The overall 5-year recurrence rate for all 3370 patients who completed the follow-up period was 2.6%. These recurrence rates are low, particularly in view of the significant number of high-risk tumors included. The only larger series of patients with BCC treated with MMS and followed up for a period of 5 years was reported by Mohs.25,26 He found an overall 5-year recurrence rate of less than 1%. Robins27 found comparable results to those reported in our study in a series of 2960 patients. In a small-scale prospective study by Julian and Bowers,28 the 5-year recurrence rate in 228 patients was 3.8% (1.7% and 4.8% for primary and recurrent tumors, respectively). Rowe, Carroll, and Day6,7 conducted a retrospective literature review of treatment modalities for BCC. They estimated that the 5-year recurrence rate for 7670 primary cases of BCC was 1.0%, whereas for 3009 previously recurrent cases it was 5.6%. They also found that the 5-year recurrence rate is more than twofold that of the short-term study (2 years). It was also demonstrated that two thirds of tumors recur in the first 3 years, and 18% recur 6 to 10 years after treatment with most modalities, which emphasizes the importance of long-term follow-up in these tumors. The general rate of recurrence of BCC correlates with several factors, such as larger tumor size, facial location in the ‘‘H-zone,’’ and more aggressive histologic subtypes.2,5,29 The main predictors of recurrence identified in our study were previous recurrence (P \ .001), a longer tumor duration (P = .015), and more levels of excision (P \ .001). The infiltrating subtype seemed to be associated with
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recurrence at 5 years; however, this was not statistically significant (P = 0.13). Tumor and defect size as well as subclinical extension were not significant predictors of recurrence in our series. Only 30.3% (3370/11,127) of the patients in our series who were initially treated with MMS completed the 5-year follow-up period. The missing data are certainly important and limit our study. Nevertheless, we believe that the information obtained after 5 years still gives a valuable estimation of the cure rate for high-risk BCC. In conclusion, this large prospective series of highrisk BCC demonstrated low 5-year recurrence rates in both primary and previously recurrent tumors. These findings emphasize the importance of tumor excision with margin control and confirm findings of previous studies that support MMS as the ‘‘gold standard,’’ in terms of cure rate, for high-risk BCC. We thank the Skin and Cancer Foundation Australia and the participating Mohs surgeons for their generosity in providing the data for this research. The Mohs surgeons involved were Drs Phillip Artemi, John Coates, Brian De’Ambrosis, Timothy Elliott, Gregory Goodman, Irene Grigoris, Dudley Hill, Shyamala Huilgol, Michelle Hunt, David Leslie, Robert Paver, Shawn Richards, William Ryman, Robert Salmon, Margaret Stewart, Howard Studniberg, Carl Vinciullo, and Perry Wilson. We also thank Emmae Ramsay (Statistician), Department of Public Health, University of Adelaide, for her help and advice in the statistical analysis of data. REFERENCES 1. Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell carcinoma. British Association of Dermatologists. Br J Dermatol 1999;141:415-23. 2. Thissen MR, Neumann MH, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol 1999;135:1177-83. 3. Kuijpers DI, Thissen MR, Neumann MH. Basal cell carcinoma: treatment options and prognosis, a scientific approach to a common malignancy. Am J Clin Dermatol 2002;3:247-59. 4. Netscher DT, Spira M. Basal cell carcinoma: an overview of tumor biology and treatment. Plast Reconstr Surg 2004; 113:74e-94e. 5. Silverman MK, Kopf AW, Bart RS, Grin CM, Levenstein MS. Recurrence rates of treated basal cell carcinomas. Part 3: Surgical excision. J Dermatol Surg Oncol 1992;18:471-6. 6. Rowe DE, Carroll RJ, Day CL Jr. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989; 15:315-28. 7. Rowe DE, Carroll RJ, Day CL Jr. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 1989;15:424-31. 8. Lawrence CM. Mohs’ micrographic surgery for basal cell carcinoma. Clin Exp Dermatol 1999;24:130-3.
9. Smeets NW, Krekels GA, Ostertag JU, Essers BA, Dirksen CD, Nieman FH, et al. Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet 2004;364:1766-72. 10. Silverman MK, Kopf AW, Gladstein AH, Bart RS, Grin CM, Levenstein MJ. Recurrence rates of treated basal cell carcinomas. Part 4: X-ray therapy. J Dermatol Surg Oncol 1992;18: 549-54. 11. Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell and squamous cell carcinomas of the skin. Int J Radiat Oncol Biol Phys 2004;60:406-11. 12. Zagrodnik B, Kempf W, Seifert B, Muller B, Burg G, Urosevic M, et al. Superficial radiotherapy for patients with basal cell carcinoma: recurrence rates, histologic subtypes, and expression of p53 and Bcl-2. Cancer 2003;98:2708-14. 13. Goette DK. Topical chemotherapy with 5-fluorouracil. J Am Acad Dermatol 1981;6:633-49. 14. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehiclecontrolled studies. J Am Acad Dermatol 2004;50:722-33. 15. Shumack S, Gebauer K, Quirk C, Macdonald K, Walters SA, Owens M. 5% imiquimod cream for the treatment of large superficial basal cell carcinoma. Arch Dermatol 2004;140:1286-7. 16. Marks R, Owens M, Walters SA. Australian Multi-Centre Trial Group. Efficacy and safety of 5% imiquimod cream in treating patients with multiple superficial basal cell carcinomas. Arch Dermatol 2004;140:1284-5. 17. Eddy DJ. Imiquimod: a potential role in dermatology? Br J Dermatol 2002;147:1-6. 18. Kalka K, Merk H, Mukhtar H. Photodynamic therapy in dermatology. J Am Acad Dermatol 2000;42:389-413. 19. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 2002;146:552-67. 20. Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE, et al. 5-Aminolevulinic acidebased photodynamic therapy. Clinical research and future challenges. Cancer 1997;79: 2282-308. 21. Thissen MR, Schroeter CA, Neumann HA. Photodynamic therapy with delta-aminolevulinic acid for nodular basal cell carcinomas using a prior debulking technique. Br J Dermatol 2000;142:338-9. 22. Morton CA. Photodynamic therapy for nonmelanoma skin cancer—and more? [Editorial] Arch Dermatol 2004;140:116-20. 23. Abide JM, Nahai F, Bennet RG. The meaning of surgical margins. Plast Reconstr Surg 1984;73:492-6. 24. Rapini RP. Comparison of methods for checking surgical margins. J Am Acad Dermatol 1990;23:288-94. 25. Mohs FE. Chemosurgery: microscopically controlled surgery for skin cancer—past, present and future. J Dermatol Surg Oncol 1978;4:41-54. 26. Mohs FE. Chemosurgery for the microscopically controlled excision of cutaneous cancer. Head Neck Surg 1978;1:150-63. 27. Robins P. Chemosurgery: my 15 years of experience. J Dermatol Surg Oncol 1981;7:779-89. 28. Julian CG, Bowers PW. A prospective study of Mohs’ micrographic surgery in two English centers. Br J Dermatol 1997;136:515-8. 29. McGovern TW, Leffell DJ. Mohs surgery: the informed view. Arch Dermatol 1999;135:1255-9.
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variety of surgical and nonsurgical treatment modalities achieve successful results in treating basal cell carcinoma (BCC). These include curettage and cautery, surgical excision, cryotherapy, radiation therapy, photodynamic therapy (PDT), topical 5-fluorouracil (5-FU), and topical imiquimod.1-4
From the Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences,a and the Department of Dermatology,b Royal Adelaide Hospital, University of Adelaide; Wakefield Clinic, Adelaidec; the Departments of Surgery and Medicine, University of Adelaided; and Skin and Cancer Foundation Australia, Sydney.e Funding sources: None. Conflict of interest: None identified. Reprints not available from the authors. Correspondence to: Dr Shyamala Huilgol, Wakefield Clinic, 270 Wakefield St, Adelaide, SA, 5000. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.087
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It is known that recurrence rates are higher for larger and previously recurrent tumors, as well as for more aggressive histologic subtypes.3-7 Standard excision has a 5-year recurrence rate of 3.2% to 10% for primary tumors, and more than 17% for recurrent BCC.3,5-7 Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation; hence it is widely used for high-risk tumors (recurrent or incompletely excised tumors, mid-facial location, [2 cm, aggressive histology, deep extension, and PNI).1,4 Reported recurrence rates with MMS are 1% to 3% for primary tumors and 5% to 7% for recurrent tumors.2,6,7 These figures are based on retrospective data and a limited number of large-scale, prospective studies.2,8,9 The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia with the aim of collecting data prospectively and involved all Mohs surgeons in the country. This article reports the outcome of patients with BCC who completed a 5-year follow-up period.
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METHOD We conducted a prospective, noncomparative, multicenter, interventional case series of patients with cutaneous BCC treated with MMS in Australia and monitored by the Skin and Cancer Foundation Australia between 1993 and 2002. All patients were treated by fellowship-trained Mohs surgeons using standard fresh-frozen MMS techniques. The general technique was based on constructing a tissue map followed by color coding of the excised tissue. Frozen sections of the entire outer margin in a continuous layer were prepared, and the tissue was stained with hematoxylin and eosin. A trained Mohs technician performed all frozen-section preparation. Residual tumor was mapped, and serial levels were excised until the surgical margins were cleared of tumor. All resections, mapping, and tissue examination were carried out by the Mohs surgeons. The decision whether to perform initial curettage for tumor debulking was made by the individual surgeons, and this was not counted as a first level of excision. In addition, surgical margin sizes for initial and subsequent layers also varied between different surgeons. The criteria for selection were all cases with BCC diagnosed histologically and treated with MMS. The following parameters were recorded: patient identification number, age, sex, reason for referral, duration of tumor, site, recurrences before MMS, preoperative tumor size, histologic classification of malignancy, evidence of perineural invasion (PNI), and postoperative defect size. Tumor and postoperative defect size were defined into 8 groups based on the maximum diameter using a straight ruler: 0-0.9 cm, 1-1.9 cm, 2-2.9 cm, 3-3.9 cm, 4-4.9 cm, 5-5.9 cm, 6-7.9 cm, 8-10 cm, and [10 cm. Subclinical extension of the tumor was calculated as the difference in number of size groups between the defect and tumor size. The primary outcome measure was BCC recurrence at 5-year follow-up for patients undergoing MMS between 1993 and 1999.
Statistical analysis Associations between categorical variables were analyzed by means of x2 tests, with the MantelHaenszel test for linear association used where appropriate. Fisher’s exact test was used if expected values were less than 5. Comparison of normally distributed variables among groups was performed by using t tests and analysis of variance; their nonparametric equivalent was used for non-normally distributed data. Exact 95% confidence intervals (CIs) were calculated for the 5-year recurrence rates.
Analyses were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS Patients with 5-year follow-up Three thousand three hundred seventy (3370) patients (1594 female and 1776 male patients) completed a 5-year follow-up period after MMS. The mean age (6 standard error of the mean) of these patients was 61 6 14 years (median, 62; range, 17-92 years). In 1886 patients (56.0%) the lesion was a primary tumor, and in 1484 patients (44.0%) the lesion was a recurrent tumor (previously treated with non-Mohs procedures). The most common stated reasons for patient referral for MMS in patients with 5-year follow-up were tumor recurrence (35.8%), tumor site (24.5%), and a poorly defined tumor (20.9%). In most patients (1732 patients, 51.4%) the tumor age before excision ranged between 1 and 5 years, and in 28.2% it was less than 1 year. Most of the tumors were located on the head and neck (98.4%). The most common anatomic site was the nose (1295 patients, 38.4%), followed by the cheek and maxilla (577 patients, 17.1%), auricular region (369 patients, 10.9%), and periocular area (366 patients, 10.9%). Tumor size was less than 2 cm in 2579 patients (76.5%), less than 1 cm in 1089 patients, and between 1.0 and 1.9 cm in 1492 patients. The postexcision defect size was less than 2 cm in 1448 patients (43.0%), whereas in the majority of patients (57.0%) it was larger than 2 cm. The percentage of patients with significant subclinical extension (defined as tumor defect exceeding tumor size by at least two size groups) was 22.1%. The most common histologic subtypes of BCC were nodulocystic (986 patients, 29.3%), infiltrating (955 patients, 28.3%), and superficial (443 patients, 13.1%). PNI was diagnosed in 76 patients who completed a 5-year follow-up period, and these data are presented in part 3 of this study. Five-year follow-up data were not available for 7757 patients. We compared the parameters of these patients with those who have 5-year follow-up data to identify differences between the two groups (Table I). Patients with no follow-up data at 5 years were less likely to have tumors on the nose (P = .08) and nodulocystic histology (P = .04). No significant differences were noted in all other parameters compared. Recurrence at 5-year follow-up Recurrence at 5-year follow-up after MMS was diagnosed in 86 of the 3370 patients (2.6%; exact 95%
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Table I. Clinical characteristics of patients with and without a 5-year follow-up period after Mohs micrographic surgery for basal cell carcinoma
Clinical feature
Male/female ratio Age, y (mean 6 SEM) Previously recurrent tumors Tumor age (1-5 y) Most common tumor sites
Patients with 5-y follow-up (N = 3370)
Patients without 5-y follow-up (N = 7757)
1.11 61 6 14
1.13 62 6 14
44.0%
43.7%
51.4% Nose (38.4%) Cheek and maxilla (17.1%) Auricular area (10.9%) Periocular region (10.3%) Tumor size \2 cm 76.5% Defect size [2 cm 57.0% Nodulocystic Most common (29.3%) histologic subtypes Infiltrating (28.3%) Superficial (13.1%)
56.7% Nose (27.6%)* Cheek and maxilla (16.3%) Auricular area (11.6%) Periocular region (13.6%) 73.4% 53.5% Nodulocystic (22.0%)y Infiltrating (31.7%) Superficial (13.8%)
SEM, Standard error of the mean. *P = .08. y P = .04.
CI, 0.02-0.031). There were 26 cases of recurrence at 5 years in the 1886 patients with primary BCC (1.4%; exact 95% CI, 0.09-0.02), and there were 60 cases of recurrence in the 1484 patients with previously recurrent BCC (4.0%; exact 95% CI, 0.031-0.052) (P\ .001 for difference in recurrence rates between primary and previously recurrent tumors). The 86 patients with recurrence at 5 years included 50 male patients (58.1%) and 36 female patients (41.9%) (P = .3). Most of these patients (52 cases, 60%) were sent for MMS with previous recurrence as the stated reason for referral. Tumor age before MMS in relation to recurrence at 5 years is presented in Table II. Recurrence at 5 years was associated with a longer tumor duration before excision (P = .015). The most common site for recurrence was the nose (38.4% of cases), followed by the cheek and maxilla (17.1%) and auricular area (10.9%) (Table III). These were also the most common sites for BCC treated by MMS, as well as for all patients with 5-year follow-up. Therefore no statistically significant association between tumor site and recurrence was found.
Table II. Tumor age before excision in patients with 5-year follow-up after Mohs micrographic surgery for basal cell carcinoma
Tumor age* (y)
\1 1-5 5-10 >10 Data not available
No recurrence at 5 y (N = 3284)
934 1683 292 110 265
(28.4%) (51.2%) (8.9%) (3.3%) (8.1%)
Recurrence at 5 y (N = 86)
16 49 15 3 3
(18.6%) (57.0%) (17.4%) (3.5%) (3.5%)
Overall cases with 5-year follow-up (N = 3370)
950 1732 307 113 268
(28.2%) (51.4%) (9.1%) (3.3%) (7.9%)
*P \ .015.
Tumor size before MMS was less than 2 cm in 66 of the patients (76.7%) with recurrence at 5 years, and in 2525 (76.6%) of the patients with no recurrence at 5 years (Table IV). No association was found between tumor size at presentation and recurrence at 5 years (P = .90). The postexcision defect size was less than 3 cm in 60 (70.0%) of the patients with recurrence at 5 years, and in 2361 (71.9%) of the patients with no recurrence at 5 years (Table V). No association was found between postexcision defect size and recurrence at 5 years (P = .17), as well as between subclinical extension and recurrence at 5 years (P = .33). The most common histologic subtypes of BCC in patients with recurrence at 5 years were infiltrating (37.2%), nodulocystic (17.4%), and superficial (13.9%) (Table VI). The infiltrating subtype appeared to be associated with recurrence at 5 years; however, this was not statistically significant (P = .13). PNI was diagnosed in 6 patients with 5-year recurrence, and the data are presented in part 3 of this study. The mean number of levels required for complete tumor excision in patients with recurrence at 5 years was 2.11 (median, 2.0; range, 1-6 levels), whereas in patients with no recurrence at 5 years it was 1.72 (median, 2.0; range 1-8 levels) (P \.001).
DISCUSSION The increase in the worldwide incidence of BCC has resulted in many studies that have evaluated different surgical and nonsurgical treatment modalities.2,3 The choice of treatment options is based on multiple variables, such as patient factors (age, sex, general health), tumor characteristics (size, location, histologic subtype), as well as the treating physician’s preference and available resources.2,3 Nonsurgical treatments commonly used for BCC include cryotherapy, radiation therapy, and topical agents (5-FU, imiquimod and PDT). Cryotherapy using liquid nitrogen was reported to achieve cure
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Table III. Sites of basal cell carcinoma in relation to 5-year recurrence in patients treated with Mohs micrographic surgery No recurrence at 5 y (N = 3284)
Site of BCC
Scalp Forehead Periocular area Auricular area Cheek and maxilla Nose Lips Chin and mandible Neck Upper limbs Trunk Genitalia Lower limbs Data not available
63 348 359 356 562
Recurrence at 5 y (N = 86)
(1.9%) (10.6%) (10.9%) (10.8%) (17.1%)
3 5 7 13 15
1260 (38.4%) 123 (3.7%) 55 (1.7%) 89 14 35 2 3 15
(3.5%) (5.8%) (8.1%) (15.1%) (17.4%)
Overall cases with 5-y follow-up (N = 3370)
66 353 366 369 577
(2.0%) (10.5%) (10.9%) (10.9%) (17.1%)
35 (40.7%) 1295 (38.4%) 3 (3.5%) 126 (3.7%) 1 (1.1%) 56 (1.7%)
(2.7%) (0.4%) (1.0%) (0.06%) (0.09%) (0.5%)
1 (1.1%) 0 2 (2.3%) 0 0 1 (1.1%)
90 14 37 2 3 16
(2.7%) (0.4%) (1.1%) (0.06%) (0.09%) (0.5%)
Table IV. Preoperative tumor sizes in relation to recurrence at 5 years in patients treated with Mohs micrographic surgery for basal cell carcinoma Tumor size* (cm)
Overall cases No recurrence Recurrence at with 5-y follow-up at 5 y (N = 3284) 5 y (N = 86) (N = 3370)
\1 1063 (32.4%) 1-1.9 1452 (44.2%) 2-2.9 445 (13.5%) 3-3.9 159 (4.8%) 4-4.9 60 (1.8%) 5-5.9 34 (1.0%) 6-7.9 8 (0.2%) 8-10 4 (0.1%) Data not 59 (1.8%) available
26 40 11 6
(30.2%) (46.5%) (12.8%) (7.0%) 0 1 (1.2%) 0 0 2 (2.3%)
1089 1492 456 165 60 35 8 4 61
(32.3%) (44.3%) (13.5%) (4.9%) (1.8%) (1.0%) (0.2%) (0.1%) (1.8%)
*P = .9.
rated as high as 99%, but these series excluded highrisk tumors such as recurrent, large, and midfacial BCCs with aggressive histologic features, which are generally accepted as a relative contraindication for treatment with cryotherapy.1-4 Radiation therapy is considered a very useful mode of treatment, especially in older and disabled patients with large tumors, when surgical treatment may not be appropriate. The estimated 5-year recurrence rate is 7.4% to 8.7% for primary BCC and 9.5% to 9.8% for recurrent tumors.6,7,10 In a recent report by Kwan, Wilson, and Moravan,11 the 4-year recurrence rate for locally advanced BCC was 14%, whereas
Table V. Postoperative defect sizes in relation to recurrence at 5 years in patients treated with Mohs micrographic surgery for basal cell carcinoma
Defect size* (cm)
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 >10 Data not available
No recurrence at 5 y (N = 3284)
111 1310 940 472 181 107 88 20 10 45
(3.4%) (39.9%) (28.6%) (14.4%) (5.5%) (3.3%) (2.7%) (0.6%) (0.3%) (1.4%)
Recurrence at 5 y (N = 86)
4 23 33 10 7 5 3
(4.6%) (26.7%) (38.4%) (11.6%) (8.1%) (5.8%) (3.5%) 0 0 1 (1.2%)
Overall cases with 5-y follow-up (N = 3370)
115 1333 973 482 188 112 91 20 10 46
(3.4%) (39.6%) (28.9%) (14.3%) (5.6%) (3.3%) (2.7%) (0.6%) (0.3%) (1.4%)
*P = .17.
Table VI. Histologic subtypes of basal cell carcinoma in relation to recurrence at 5 years in patients treated with Mohs micrographic surgery
Histologic subtype
Nodulocystic Infiltrating* Superficial Morpheic Micronodular Basosquamous Combined subtypes Data not available
No recurrence Recurrence at 5 y (N = 3284) at 5 y (N = 86)
971 923 431 246 138 94 37
(29.6%) (28.1%) (13.1%) (7.5%) (4.2%) (2.9%) (1.1%)
444 (13.5%)
15 32 12 10 3 4 2
(17.4%) (37.2%) (13.9%) (11.6%) (3.5%) (4.7%) (2.3%)
8 (9.3%)
Overall cases with 5-y follow-up (N = 3370)
986 955 443 256 141 98 39
(29.3%) (28.3%) (13.1%) (7.6%) (4.2%) (2.9%) (1.2%)
452 (13.4%)
*P = .13.
Zagrodnik et al12 reported an estimated 5-year recurrence rate of 8.2% for nodular BCC and 26.1% to 27.7% for superficial and sclerosing BCC. The main disadvantage of this treatment is the lack of tumor margin control and the potential side effect, especially in the periocular region (cataract, dry eye, and lacrimal duct obstruction).1,4 Topical 5-FU is useful for low-risk and nonfacial BCC and is generally used for treating multiple superficial BCCs on the trunk and lower extremities.1,13 Imiquimod 5% is a new immune-modulating drug that stimulates monocytes and dendritic cells to produce interferon alfa and other cytokines. Recent publications demonstrate efficacy of this drug in short-term clearance of superficial BCC,14-17 but long-term recurrence rates have not yet been
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Table VII. Comparative clinical and 5-year recurrence data on Mohs micrographic surgery for basal cell carcinoma Mohs25,26
Study years Tumor location Overall No. of tumors with 5-y follow-up (primary/secondary) Overall 5-y recurrence (primary/secondary)
Robins27
Julian and Bowers28
Current study
NA Head 8643 (7257/1386)
1965-1980 Head 2960 (NA)
1981-1995 Head 228 (NA)
1993-2002 Mainly head and neck 3370 (1886/ 1484)
1.0% (0.7%/3.2%)
2.6% (1.8%/3.4%)
3.8% (1.7%/4.8%)
2.6% (1.4%/ 4.0%)
NA, Not available.
assessed. Topical PDT is based on application of the porphyrin aminolevulinic acid to the tumor, which is absorbed and makes the lesion photosensitive. Photodestruction is achieved with exposure to light with a wavelength of 620 to 670 nm.3 An important determinant of response to treatment is tumor thickness; Aminolevulinic acidePDT was shown to be effective in treating superficial BCC, with short-term clearance rates of 87% to 100%, whereas nodular BCC had lower rates of 10% to 70% and required prior debulking to enhance the response to treatment.18-21 Morpheic and pigmented lesions seem to respond poorly to PDT.20 There are no 5-year follow-up data, but short-term results for superficial BCC are encouraging.22 Surgical excision is the most frequent treatment modality for BCC. Excision of BCC without margin control is estimated to result in a 5-year recurrence rate of 3.2% to 10.0% for primary tumors and more than 17% for recurrent BCC.3,5-7 In a review of 2606 patients with primary BCC treated with surgical excision and followed up for 5 years, Rowe, Carroll, and Day6 calculated a 5-year recurrence rate of 10.1%, whereas in 522 patients with previously recurrent tumors the recurrence rate was 17.4%. Standard histologic assessment of excision specimens with breadloaf sectioning examines only 0.2% of the margins. In contrast, MMS utilizes en-face sections of the entire outer surface of the excised tissue, thereby examining close to 100% of the peripheral and deep margins.3,23,24 It is generally accepted that MMS is indicated in the treatment of high-risk tumors; these are usually tumors with risk factors such as previous recurrence, midfacial location (periocular area, nose, and lips), size larger than 2 cm, or aggressive histology (morpheic, infiltrative, basosquamous, or micronodular). Additional factors include deep invasion, PNI, incompletely excised tumors, and clinically indistinct borders.1,3 A limited number of large-scale or prospective studies were conducted previously to evaluate the
role of MMS in treating BCC (Table VII). Our study, which is based on the Australian MMS database, is the largest reported prospective nationwide series of patients with BCC managed by MMS and followed up for 5 years. Our series is characterized by a high percentage of large head and neck, as well as recurrent, tumors, which are considered more aggressive and are classified as high-risk tumors.1 The 5-year recurrence rate in primary cases was 1.4%, whereas in previously recurrent cases it was 4.0%. The overall 5-year recurrence rate for all 3370 patients who completed the follow-up period was 2.6%. These recurrence rates are low, particularly in view of the significant number of high-risk tumors included. The only larger series of patients with BCC treated with MMS and followed up for a period of 5 years was reported by Mohs.25,26 He found an overall 5-year recurrence rate of less than 1%. Robins27 found comparable results to those reported in our study in a series of 2960 patients. In a small-scale prospective study by Julian and Bowers,28 the 5-year recurrence rate in 228 patients was 3.8% (1.7% and 4.8% for primary and recurrent tumors, respectively). Rowe, Carroll, and Day6,7 conducted a retrospective literature review of treatment modalities for BCC. They estimated that the 5-year recurrence rate for 7670 primary cases of BCC was 1.0%, whereas for 3009 previously recurrent cases it was 5.6%. They also found that the 5-year recurrence rate is more than twofold that of the short-term study (2 years). It was also demonstrated that two thirds of tumors recur in the first 3 years, and 18% recur 6 to 10 years after treatment with most modalities, which emphasizes the importance of long-term follow-up in these tumors. The general rate of recurrence of BCC correlates with several factors, such as larger tumor size, facial location in the ‘‘H-zone,’’ and more aggressive histologic subtypes.2,5,29 The main predictors of recurrence identified in our study were previous recurrence (P \ .001), a longer tumor duration (P = .015), and more levels of excision (P \ .001). The infiltrating subtype seemed to be associated with
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recurrence at 5 years; however, this was not statistically significant (P = 0.13). Tumor and defect size as well as subclinical extension were not significant predictors of recurrence in our series. Only 30.3% (3370/11,127) of the patients in our series who were initially treated with MMS completed the 5-year follow-up period. The missing data are certainly important and limit our study. Nevertheless, we believe that the information obtained after 5 years still gives a valuable estimation of the cure rate for high-risk BCC. In conclusion, this large prospective series of highrisk BCC demonstrated low 5-year recurrence rates in both primary and previously recurrent tumors. These findings emphasize the importance of tumor excision with margin control and confirm findings of previous studies that support MMS as the ‘‘gold standard,’’ in terms of cure rate, for high-risk BCC. We thank the Skin and Cancer Foundation Australia and the participating Mohs surgeons for their generosity in providing the data for this research. The Mohs surgeons involved were Drs Phillip Artemi, John Coates, Brian De’Ambrosis, Timothy Elliott, Gregory Goodman, Irene Grigoris, Dudley Hill, Shyamala Huilgol, Michelle Hunt, David Leslie, Robert Paver, Shawn Richards, William Ryman, Robert Salmon, Margaret Stewart, Howard Studniberg, Carl Vinciullo, and Perry Wilson. We also thank Emmae Ramsay (Statistician), Department of Public Health, University of Adelaide, for her help and advice in the statistical analysis of data. REFERENCES 1. Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell carcinoma. British Association of Dermatologists. Br J Dermatol 1999;141:415-23. 2. Thissen MR, Neumann MH, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol 1999;135:1177-83. 3. Kuijpers DI, Thissen MR, Neumann MH. Basal cell carcinoma: treatment options and prognosis, a scientific approach to a common malignancy. Am J Clin Dermatol 2002;3:247-59. 4. Netscher DT, Spira M. Basal cell carcinoma: an overview of tumor biology and treatment. Plast Reconstr Surg 2004; 113:74e-94e. 5. Silverman MK, Kopf AW, Bart RS, Grin CM, Levenstein MS. Recurrence rates of treated basal cell carcinomas. Part 3: Surgical excision. J Dermatol Surg Oncol 1992;18:471-6. 6. Rowe DE, Carroll RJ, Day CL Jr. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989; 15:315-28. 7. Rowe DE, Carroll RJ, Day CL Jr. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 1989;15:424-31. 8. Lawrence CM. Mohs’ micrographic surgery for basal cell carcinoma. Clin Exp Dermatol 1999;24:130-3.
9. Smeets NW, Krekels GA, Ostertag JU, Essers BA, Dirksen CD, Nieman FH, et al. Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet 2004;364:1766-72. 10. Silverman MK, Kopf AW, Gladstein AH, Bart RS, Grin CM, Levenstein MJ. Recurrence rates of treated basal cell carcinomas. Part 4: X-ray therapy. J Dermatol Surg Oncol 1992;18: 549-54. 11. Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell and squamous cell carcinomas of the skin. Int J Radiat Oncol Biol Phys 2004;60:406-11. 12. Zagrodnik B, Kempf W, Seifert B, Muller B, Burg G, Urosevic M, et al. Superficial radiotherapy for patients with basal cell carcinoma: recurrence rates, histologic subtypes, and expression of p53 and Bcl-2. Cancer 2003;98:2708-14. 13. Goette DK. Topical chemotherapy with 5-fluorouracil. J Am Acad Dermatol 1981;6:633-49. 14. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehiclecontrolled studies. J Am Acad Dermatol 2004;50:722-33. 15. Shumack S, Gebauer K, Quirk C, Macdonald K, Walters SA, Owens M. 5% imiquimod cream for the treatment of large superficial basal cell carcinoma. Arch Dermatol 2004;140:1286-7. 16. Marks R, Owens M, Walters SA. Australian Multi-Centre Trial Group. Efficacy and safety of 5% imiquimod cream in treating patients with multiple superficial basal cell carcinomas. Arch Dermatol 2004;140:1284-5. 17. Eddy DJ. Imiquimod: a potential role in dermatology? Br J Dermatol 2002;147:1-6. 18. Kalka K, Merk H, Mukhtar H. Photodynamic therapy in dermatology. J Am Acad Dermatol 2000;42:389-413. 19. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa H, et al. Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group. Br J Dermatol 2002;146:552-67. 20. Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE, et al. 5-Aminolevulinic acidebased photodynamic therapy. Clinical research and future challenges. Cancer 1997;79: 2282-308. 21. Thissen MR, Schroeter CA, Neumann HA. Photodynamic therapy with delta-aminolevulinic acid for nodular basal cell carcinomas using a prior debulking technique. Br J Dermatol 2000;142:338-9. 22. Morton CA. Photodynamic therapy for nonmelanoma skin cancer—and more? [Editorial] Arch Dermatol 2004;140:116-20. 23. Abide JM, Nahai F, Bennet RG. The meaning of surgical margins. Plast Reconstr Surg 1984;73:492-6. 24. Rapini RP. Comparison of methods for checking surgical margins. J Am Acad Dermatol 1990;23:288-94. 25. Mohs FE. Chemosurgery: microscopically controlled surgery for skin cancer—past, present and future. J Dermatol Surg Oncol 1978;4:41-54. 26. Mohs FE. Chemosurgery for the microscopically controlled excision of cutaneous cancer. Head Neck Surg 1978;1:150-63. 27. Robins P. Chemosurgery: my 15 years of experience. J Dermatol Surg Oncol 1981;7:779-89. 28. Julian CG, Bowers PW. A prospective study of Mohs’ micrographic surgery in two English centers. Br J Dermatol 1997;136:515-8. 29. McGovern TW, Leffell DJ. Mohs surgery: the informed view. Arch Dermatol 1999;135:1255-9.