- Email: [email protected]
Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years
DERMATOLOGIC
SURGERY
Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years 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: Only a few prospective studies have been published on surgical treatments for cutaneous basal cell carcinoma (BCC). Objective: Our purpose was to report the clinical findings of all patients with BCC treated with Mohs micrographic surgery (MMS) in Australia between 1993 and 2002. 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. The main outcome measures were patient demographics, reason for referral, duration of tumor, site, preoperative tumor size, recurrences before MMS, histologic classification of malignancy, and postoperative defect size. Results: The study included 11,127 patients (47% females and 53% males) with a mean age of 62 years (range, 15-98 years). In 43.8% of cases BCC was a recurrent tumor. Most of the tumors (98.3%) were on the head and neck area, most commonly on the nose (39%), cheek and maxilla (16.5%), periocular area (12.7%), and auricular region (11.4%). The most common histologic subtypes were infiltrating (30.7%), nodulocystic (24.2%), and superficial (13.6%). Previously recurrent tumors were larger than primary tumors (P \ .001), had a larger postexcision defect and more subclinical extension, and required more levels of excision (P \ .001). Limitations: Data were missing for some outcome measures. Conclusion: This large prospective series of BCC managed by MMS is characterized by a high percentage of high-risk tumors. Most tumors were located in the mid-facial area and the histologic subtype was mainly infiltrating or nodulocystic. That previously recurrent tumors were larger and demonstrated a more extensive subclinical extension compared with primary tumors emphasizes the importance of initial tumor eradication with margin control. ( J Am Acad Dermatol 2005;53:445-51.)
B
asal cell carcinoma (BCC) is the most common malignancy among white persons in the United States and Australia.1-5 The reported
From the Oculoplastic & Orbital Division, Department of Ophthalmology & Visual Sciencesa 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 the Skin & 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]. gov.au. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.083
incidence in Australia is 726 per 100,000 population,6 but in some northern parts of Australia it is twice as high.7 BCC most often arises in areas of long-term sun exposure, with a high predilection for the head and neck area. Although most BCCs are indolent and slowly progressive tumors, they can be locally aggressive and, in rare instances, metastasize.1-5 This requires complete tumor removal, but with concern given to preservation of function and normal tissue, as well as cosmesis.8 There are several surgical and nonsurgical treatment modalities for BCC that achieve tumor eradication and provide high cure rates, but they lack the ability to define tumor margins. Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation 445
446 Leibovitch et al
J AM ACAD DERMATOL SEPTEMBER 2005
Table I. Prior treatments for recurrent basal cell carcinoma Prior treatments (No. of patients) No. of tx
Cryotherapy (N = 2235)
1 2 3 $4
994 684 204 353
(44.5%) (30.6%) (9.1%) (5.8%)
Curettage and cautery (N = 955)
746 131 24 54
Surgical excision (N = 2662)
(78.1%) (13.7%) (2.5%) (5.7%)
1923 530 122 87
(72.2%) (19.9%) (4.6%) (3.3%)
RT (N = 199)
191 3 1 4
(96.0%) (1.5%) (0.5%) (2.0%)
RT, Radiation therapy; tx, treatments.
Table II. Reason stated for referral for Mohs micrographic surgery Reason for referral
Recurrent tumor Tumor site Poorly defined tumor Tumor type Incomplete tumor excision Tumor size No details available
Primary BCC (N = 6252)
— 2490 (39.8%) 1982 (31.7%) 898 (14.4%) 603 (9.6%) 22 (0.4%) 257 (4.1%)
hence it is widely used for high-risk tumors and on the head and neck (recurrent or incompletely excised tumors, mid-facial location, [2 cm, aggressive histologic features, and deep and perineural invasion).9 The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia (SCFA) with the aim of collecting prospective data and involved all Mohs surgeons in the country. This first article describes all patients with BCC, treated with MMS, who were monitored by the SCFA between 1993 and 2002. The next two parts report the outcome in patients with 5-year follow-up (part 2) and the incidence, features, and outcomes of patients with perineural invasion (part 3).
METHOD We conducted a prospective, noncomparative, multicenter, interventional case series of patients with cutaneous BCC treated with MMS in Australia and monitored by the SCFA between 1993 and 2002. The selection criteria were all cases with histologically confirmed BCC and treated with MMS. The main data recorded were patient age and sex, reason for referral, duration of tumor, site, recurrences before MMS, preoperative tumor size, histologic classification of malignancy, number of excision levels, and postoperative defect size. Tumor and postoperative defect size were defined into 8 size 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 tumor extension
Previously recurrent BCC (N = 4875)
3681 253 454 148 162 1 176
(75.5%) (5.2%) (9.3%) (3.0%) (3.3%) (0.02%) (3.6%)
Overall (N = 11,127)
3681 2743 2436 1046 765 23 433
(33.1%) (24.6%) (21.9%) (9.4%) (6.9%) (0.2%) (3.9%)
is defined as the size difference between the clinical margin and the histologically clear margins. In our study, we defined the subclinical extension of the tumor as the difference in number of size groups between the defect and tumor size. All surgeons were 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 final histologic diagnosis was done on a debulking specimen before Mohs surgery or on the frozen sections seen on the routine Mohs surgical sections (or both), according to the surgeon’s preferences. In several centers, the final histologic specimens were also reviewed by an experienced dermatopathologist. Statistical analysis Associations between categorical variables were analyzed by means of x2 tests, with the MantelHaenszel test for linear association used where
Leibovitch et al 447
J AM ACAD DERMATOL VOLUME 53, NUMBER 3
Table III. Tumor age before excision in patients with basal cell carcinoma treated with Mohs micrographic surgery Tumor age* (y)
\1 1-5 5-10 [10 Data not available
Primary BCC (N = 6252)
2562 3122 119 44 405
(41.0%) (49.9%) (1.9%) (0.7%) (6.5%)
Previously recurrent BCC (N = 4875)
393 3005 934 334 209
(8.1%) (61.6%) (19.2%) (6.9%) (4.3%)
Overall (N = 11,127)
2955 6127 1053 378 614
(26.6%) (55.1%) (9.5%) (3.4%) (5.5%)
*P \ .001.
Table IV. Sites of basal cell carcinoma treated with Mohs micrographic surgery Site of BCC
Scalp Forehead Periocular region Auricular area Cheek and maxilla Nose Lips Chin and mandible Neck Upper limbs Trunk Genital Lower limbs Data not available
Primary tumors (N = 6252)
119 590 935 725 789 2540 295 85 90 18 35 2 7 27
(1.9%) (9.4%) (14.9%) (11.6%) (12.6%) (40.6%) (4.7%) (1.4%) (1.4%) (0.3%) (0.6%) (0.03%) (0.1%) (0.4%)
appropriate. Fisher’s exact test was used if expected values were less than 5. Comparison of normally distributed variables among groups was performed using t tests and analysis of variance; their nonparametric equivalent was used for non-normally distributed data. Analyses were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS The study group included 11,127 patients who underwent MMS for BCC between 1993 and 2002. There were 5231 female patients (47.1%) and 5886 male patients (52.9%) (P = .7), whose mean age was 62 6 14 years (median, 64 years; range, 15-98 years). In 6252 patients (56.2%), the lesion was a primary nonrecurrent tumor, and in 4875 patients (43.8%) the lesion was a recurrent tumor (previously treated with non-Mohs procedures; Table I). The most commonly stated reasons for patient referral for MMS was tumor recurrence (33.1%) and tumor site (24.6%) (Table II). Patients were mainly referred by a dermatologist (52.3%) or a general practitioner (37.7%). In most patients (6127 patients, 55.1%) the tumor age before excision ranged be-
Previously recurrent tumor (N = 4875)
64 410 483 543 1050 1806 183 42 140 25 87 1 10 26
(1.3%) (8.4%) (9.9%) (11.1%) (21.5%) (37.0%) (3.7%) (0.9%) (2.9%) (0.5%) (1.8%) (0.02%) (0.2%) (0.5%)
Overall (N = 11,127)
183 1000 1418 1268 1839 4346 478 127 230 43 122 3 17 53
(1.6%) (8.9%) (12.7%) (11.4%) (16.5%) (39.1%) (4.3%) (1.1%) (2.1%) (0.4%) (1.1%) (0.03%) (0.2%) (0.5%)
tween 1 and 5 years. As expected, previously recurrent tumors were present for a longer period (P \ .001; Table III). Most of the tumors were located on the head and neck (98.3%). The most common anatomic site for BCC was the nose (39.1%), followed by the cheek and maxilla (16.5%), periocular area (12.7%), and auricular region (11.4%). These were also the most common sites in each of the primary and recurrent BCC groups separately (Table IV). Tumor size before MMS was less than 2 cm in 8276 patients (74.4%); in 3358 patients it was less than 1 cm, and in 4918 patients it was between 1 and 1.9 cm (Table V). Previously recurrent tumors were larger than primary tumors (P \ .001). The postexcision defect size was less than 2 cm in 4667 patients only (41.9%), whereas in the majority of patients (58.1%), it was larger than 2 cm (Table VI). Defect sizes in previously recurrent tumors were larger than primary tumors (P \ .001). The subclinical tumor extension (the difference in number of size groups between the final postoperative defect and preoperative clinical tumor size) is presented in Table VII. Significant subclinical extension, defined
448 Leibovitch et al
J AM ACAD DERMATOL SEPTEMBER 2005
Table V. Preoperative tumor sizes in relation to prior recurrence in patients with basal cell carcinoma treated with Mohs micrographic surgery Tumor size* (cm)
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 Data not available
Primary BCC (N = 6252)
2331 2824 720 203 70 17 10 20 57
(37.3%) (45.2%) (11.5%) (3.2%) (1.1%) (0.3%) (0.2%) (0.3%) (0.9%)
Previously recurrent BCC (N = 4875)
1027 2094 959 338 165 48 20 63 161
(21.1%) (42.9%) (20.3%) (6.9%) (3.4%) (1.0%) (0.4%) (1.3%) (3.3%)
Overall (N = 11,127)
3358 4918 1679 541 235 65 30 83 218
(30.2%) (44.2%) (15.1%) (4.9%) (2.1%) (0.6%) (0.3%) (0.7%) (2.0%)
*P \ .001.
Table VI. Postoperative defect sizes in relation to prior recurrence in patients with basal cell carcinoma treated with Mohs micrographic surgery 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
Primary BCC (N = 6252)
348 2877 1740 736 256 115 62 23 11 84
(5.6%) (46.0%) (27.8%) (11.8%) (4.1%) (1.8%) (1.0%) (0.4%) (0.2%) (1.3%)
Previously recurrent BCC (N = 4875)
89 1353 1463 891 418 257 155 115 35 99
(1.8%) (27.7%) (30.0%) (18.3%) (8.6%) (5.3%) (3.2%) (2.4%) (0.7%) (2.0%)
Overall (N = 11,127)
437 4230 3203 1627 674 372 217 138 46 183
(3.9%) (38.0%) (28.8%) (14.6%) (6.1%) (3.3%) (1.9%) (1.2%) (0.4%) (1.6%)
*P \ .001.
as tumor defect exceeding tumor size by at least two size groups, was seen in 14.1% of primary tumors and in 26.7% of previously recurrent tumors (P \ .0001). The overall percentage of patients with significant subclinical extension was 20.3% (Table VII). Several anatomic sites (temple, auricular area, periocular area, nose, neck, and trunk) were also associated with a significant subclinical extension (P \.0001). The most common histologic subtypes of BCC were infiltrating (3417 patients, 30.7%), nodulocystic (2693 patients, 24.2%), and superficial (1510 patients, 13.6%). Similar proportions were noted in the primary and recurrent tumor groups (Table VIII). The morpheic subtype was more common in the female patients, whereas the basosquamous subtype was more common in the male patients (P \ .001). The infiltrating and morpheic histologic subtypes were associated with larger tumor and defect sizes, as well as significant subclinical extension (P \ .0001, P \ .0001, and P = .0006, respectively, for each of the subtypes). Perineural invasion
was diagnosed in 283 patients; 20 of them were treated with adjunctive radiation therapy. Data on perineural invasion are presented in part 3 of this study. The mean number of levels required for complete tumor excision was 1.73 (median, 2.0; range, 1-9 levels). Recurrent cases required more levels of excision (mean, 1.86; range, 1-9) compared with primary cases (mean, 1.63; range, 1-8) (P \ .001). Morpheic BCC and infiltrating BCC required more levels (mean, 2.04 and 1.98, respectively; P \.0001). Three thousand three hundred seventy patients (3370) completed a 5-year follow-up period. The data on these patients are presented in part 2 of this study.
DISCUSSION BCC is a common skin tumor, predominantly found on sun-exposed areas in fair-skinned persons.1,2 Although patients usually present with BCC in the fifth to eighth decades of life, the age range may be much wider, and there are reports of
Leibovitch et al 449
J AM ACAD DERMATOL VOLUME 53, NUMBER 3
Table VII. Subclinical extension (difference between tumor and defect sizes) in relation to previous recurrence of basal cell carcinoma Difference between tumor and defect size (number of size categories)
Primary BCC (N = 6074) Recurrent BCC (N = 4565) Total (N = 10,639)*
0
1
2
31
1835 (30.2%) 1153 (25.3%) 2988 (28.1%)
3380 (55.6%) 2193 (48.0%) 5573 (52.4%)
669 (11.0%) 805 (17.6%) 1474 (13.8%)
190 (3.1%) 414 (9.1%) 694 (6.5%)
0, Same size category for tumor and defect; 1, one size category difference between tumor and defect; 2, two size category difference between tumor and defect; 31, 3 or more size category difference between tumor and defect. *Data not available for 488 patients (4.4%).
Table VIII. Histologic subtypes of basal cell carcinoma treated with Mohs micrographic surgery Histologic subtype
Infiltrating Nodulocystic Superficial Morpheic Micronodular Basosquamous Combined subtypes Data not available
Primary BCC (N = 6252)
1848 1620 699 498 252 93 24 1218
(29.6%) (25.9%) (11.2%) (8.0%) (4.0%) (1.5%) (0.4%) (19.5%)
tumors occurring in the second decade of life.2,10,11 In most series there appears to be a male predominance.2,10,12,13 In our study, there were more male patients treated (52.9%) than female patients, but this was not statistically significant (P = .7). The mean age was 62 6 14 years (ranging between 15 and 98 years), similar to findings of previous reports. BCC is most commonly seen on the head and neck, mainly involving the central area of the face. In a large retrospective series by Scrivener, Grosshans, and Cribier10 of 13,457 patients with BCC at a dermatopathology referral center in France, 85% of the tumors were located on the head and neck. Bastiaens et al12 found that approximately 70% of cases occurred on the head and neck area in a series of patients in the Netherlands. Similar frequencies were reported by other authors reporting series from different geographical areas.2,14 Analysis of the anatomic distribution in our series showed that more than 98% of tumors were located on the head and neck, most commonly on the nose (39.1%), followed by the cheek and maxilla (16.5%), periocular area (12.7%), and auricular region (11.4%). Only 185 cases (1.7%) were found on other body areas. The predilection for the head and neck may be explained by higher sun exposure. In our series, there may also be a referral bias for treatment with Mohs surgery for mid-facial BCCs as they are higher risk tumors.4
Previously recurrent BCC (N = 4875)
1569 1073 811 359 227 85 37 714
(32.2%) (22.0%) (16.6%) (7.4%) (4.7%) (1.7%) (0.8%) (14.6%)
Overall (N = 11,127)
3417 2693 1510 857 479 178 61 1932
(30.7%) (24.2%) (13.6%) (7.7%) (4.3%) (1.6%) (0.5%) (17.4%)
The clinical and histologic presentations of BCC are varied. Clinically, it is usually slowly progressive, presenting as a papule, nodule, plaque, ulcer (‘‘rodent ulcer’’) or cyst. The color is usually red to white but may be blue-black. There is a characteristic ‘‘pearly’’ translucence to most lesions when placed on the stretch and overlying telangiectases are common.2 A small percentage of lesions aggressively invade deeper tissues and some rare cases metastasize.2,4 Histologically, BCC is composed of islands or nests of basaloid cells with peripheral palisading and frequent mitotic figures. Several subtypes of BCC have clinical importance.2,4,15 The nodular type is the most common and least invasive, accounting for 70% of cases. It shows typical peripheral palisading and includes a nodulocystic variant with central mucin accumulation. The micronodular subtype is composed of small round tumor islands and has a greater propensity for subclinical extension and local recurrence.2 The superficial subtype is less aggressive and accounts for 10% to 15% of cases. It exhibits an irregular proliferation of tumor cells attached to an atrophic epidermis with almost no penetration to the dermis.12 The least common but more aggressive subtypes are morpheic, infiltrating, and basosquamous; together they account for 15% of cases.2,4 The morpheic subtype shows strands of atypical basaloid cells embedded in a dense fibrous stroma, whereas
450 Leibovitch et al
J AM ACAD DERMATOL SEPTEMBER 2005
in the infiltrating type these cell strands are only a few layers thick and with almost no peripheral palisading.12 The basosquamous variant is characterized by areas of BCC with typical basaloid cells and areas of squamous cell carcinoma differentiation, having a transition zone with intermediate cells in between.2 In our study, the most common histologic subtypes of BCC were infiltrating (30.7%), nodulocystic (24.2%), and superficial (13.6%) (Table VIII). Overall, the 3 more aggressive subtypes (morpheic, infiltrating and basosquamous) accounted for 40% of cases, which is much higher than the 15% commonly cited in the literature.2 This relatively high proportion of aggressive subtypes is undoubtedly influenced by referral bias for MMS. As demonstrated in Table II, more than 30% of cases were referred to MMS because of tumor histology or a poorly defined lesion, which is more common with these subtypes and may explain their relative preponderance. We also found that the infiltrating and morpheic histologic subtypes were associated with larger tumor size, defect size, as well as significant subclinical extension (P \ .0001, P \ .0001, and P = .0006, respectively, for each of the subtypes). In addition, these two subtypes of BCC required more Mohs levels (P\.0001). Batra and Kelley16 described 868 patients with BCC and found that morpheic tumors were 2.3 times (P \.001) as likely to exhibit extensive subclinical extension compared with primary nodular BCC. These findings emphasize the increased local invasiveness of these histologic subtypes. There were 4874 patients in our series with recurrent tumors, all of whom had been treated previously with modalities other than MMS (Table I). Previously recurrent tumors were larger than primary tumors (P \ .001), required more levels of excision (P \.001), and the postexcision defect sizes were larger (P \.001). Significant extension, defined as tumor defect exceeding tumor size by at least two size groups, was seen in 14.1% of primary tumors and in 26.7% of previously recurrent tumors (P \ .0001). That recurrent tumors are associated with significant subclinical extension has been shown in previous studies. Batra and Kelley16 found that recurrent tumors were 3.2 times (P \ 0.001) as likely to exhibit extensive subclinical extension compared with primary BCC. They also found that larger tumors were associated with more extensive subclinical extension. The significant subclinical extension in our series further emphasizes the importance of margin-controlled excision for BCC and may explain the failure rate in some of the non-MMS treatment modalities, which are based solely on clinical margins with no histologic control. Furthermore,
previously recurrent lesions treated with destructive modalities such as cryotherapy may have architectural changes that make margin-control excision very difficult. Recurrent or incompletely excised tumors are contributing factors to more aggressive behavior of BCC.4 Lang and Maize17 reported that 65% of recurrent BCCs demonstrated aggressive histologic subtypes. It has been postulated by Richmond and Devie18 that incomplete excision may also contribute to the evolution of an aggressive BCC phenotype in part due to the presence of scar tissue, which obscures monitoring and delays clinical detection of recurrence. In addition, the fibrosis may entrap malignant cells and favor deep extension by preventing upward migration. It is also possible that tumors with more aggressive histologic subtypes are more likely to be incompletely excised particularly when unmonitored excision is used. These findings further emphasize the importance of early detection of BCC and treatment with margin control to reduce the risk of recurrence. In conclusion, this study is the largest reported prospective nationwide series of BCC managed by MMS. This series is characterized by a high percentage of head and neck cases as well as recurrent cases. In addition, a significant number of patients had large tumors. These factors contribute to a more aggressive nature and define BCCs as high-risk tumors.5 The most common histologic subtypes were infiltrating and nodulocystic BCC. The nose, cheek and maxilla, periocular area, and auricular region were most commonly affected. Previously recurrent tumors were larger than primary tumors, had a larger postexcision defect, a more extensive subclinical extension, and required more levels of excision. We thank the Skin and Cancer Foundation Australia and 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. Wong CSM, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003;327:794-8. 2. Weedon D. Tumors of the epidermis. In: Skin pathology. London: Churchill-Livingstone; 1997. pp. 648-51. 3. Miller SJ. Biology of basal cell carcinoma (Part I). J Am Acad Dermatol 1991;24:1-13.
J AM ACAD DERMATOL
Leibovitch et al 451
VOLUME 53, NUMBER 3
4. Walling HW, Fosko SW, Geraminejad PA, Whitaker DC. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev 2004;23:389-402. 5. 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. 6. Marks R, Staples M, Giles G. Trends in non-melanocytic skin cancer treated in Australia: the second national survey. Int J Cancer 1993;53:585-90. 7. Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population. Int J Cancer 1990; 46:356-61. 8. Netscher DT, Spira M. Basal cell carcinoma: an overview of tumor biology and treatment. Plast Reconstr Surg 2004; 113:74e-94e. 9. Shriner DL, McCoy DK, Goldberg DJ, Wagner RF Jr. Mohs micrographic surgery. J Am Acad Dermatol 1998;39:79-97. 10. Scrivener Y, Grosshans E, Cribier B. Variations of basal cell carcinomas according to gender, age, location and histopathological subtype. Br J Dermatol 2002;147:41-7. 11. Rahbari H, Mehregan AH. Basal cell epithelioma (carcinoma) in children and teenagers. Cancer 1982;49:350-3.
12. Bastiaens MT, Hoefnagel JJ, Bruijn JA, Westendorp RG, Vermeer BJ, Bouwes Bavinck JN. Differences in age, site distribution and sex between nodular and superficial basal cell carcinomas indicate different type of tumors. J Invest Dermatol 1998;110:880-4. 13. Tran H, Chen K, Shumack S. Epidemiology and aetiology of basal cell carcinoma. Br J Dermatol 2003;149:50-2. 14. Kopf AW. Computer analysis of 3531 basal cell carcinomas of the skin. J Dermatol 1979;6:267-81. 15. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol 1990; 23:1118-26. 16. Batra RS, Kelley LC. Predictors of extensive subclinical spread in nonmelanoma skin cancer treated with Mohs micrographic surgery. Arch Dermatol 2002;138:1043-51. 17. Lang PG Jr, Maize JC. Histologic evolution of recurrent basal cell carcinoma and treatment implications. J Am Acad Dermatol 1986;14:186-96. 18. Richmond J, Devie RM. The significance of incomplete excision in patients with basal cell carcinoma. Br J Plast Surg 1987; 40:63-7.
SURGERY
Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years 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: Only a few prospective studies have been published on surgical treatments for cutaneous basal cell carcinoma (BCC). Objective: Our purpose was to report the clinical findings of all patients with BCC treated with Mohs micrographic surgery (MMS) in Australia between 1993 and 2002. 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. The main outcome measures were patient demographics, reason for referral, duration of tumor, site, preoperative tumor size, recurrences before MMS, histologic classification of malignancy, and postoperative defect size. Results: The study included 11,127 patients (47% females and 53% males) with a mean age of 62 years (range, 15-98 years). In 43.8% of cases BCC was a recurrent tumor. Most of the tumors (98.3%) were on the head and neck area, most commonly on the nose (39%), cheek and maxilla (16.5%), periocular area (12.7%), and auricular region (11.4%). The most common histologic subtypes were infiltrating (30.7%), nodulocystic (24.2%), and superficial (13.6%). Previously recurrent tumors were larger than primary tumors (P \ .001), had a larger postexcision defect and more subclinical extension, and required more levels of excision (P \ .001). Limitations: Data were missing for some outcome measures. Conclusion: This large prospective series of BCC managed by MMS is characterized by a high percentage of high-risk tumors. Most tumors were located in the mid-facial area and the histologic subtype was mainly infiltrating or nodulocystic. That previously recurrent tumors were larger and demonstrated a more extensive subclinical extension compared with primary tumors emphasizes the importance of initial tumor eradication with margin control. ( J Am Acad Dermatol 2005;53:445-51.)
B
asal cell carcinoma (BCC) is the most common malignancy among white persons in the United States and Australia.1-5 The reported
From the Oculoplastic & Orbital Division, Department of Ophthalmology & Visual Sciencesa 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 the Skin & 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]. gov.au. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.083
incidence in Australia is 726 per 100,000 population,6 but in some northern parts of Australia it is twice as high.7 BCC most often arises in areas of long-term sun exposure, with a high predilection for the head and neck area. Although most BCCs are indolent and slowly progressive tumors, they can be locally aggressive and, in rare instances, metastasize.1-5 This requires complete tumor removal, but with concern given to preservation of function and normal tissue, as well as cosmesis.8 There are several surgical and nonsurgical treatment modalities for BCC that achieve tumor eradication and provide high cure rates, but they lack the ability to define tumor margins. Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation 445
446 Leibovitch et al
J AM ACAD DERMATOL SEPTEMBER 2005
Table I. Prior treatments for recurrent basal cell carcinoma Prior treatments (No. of patients) No. of tx
Cryotherapy (N = 2235)
1 2 3 $4
994 684 204 353
(44.5%) (30.6%) (9.1%) (5.8%)
Curettage and cautery (N = 955)
746 131 24 54
Surgical excision (N = 2662)
(78.1%) (13.7%) (2.5%) (5.7%)
1923 530 122 87
(72.2%) (19.9%) (4.6%) (3.3%)
RT (N = 199)
191 3 1 4
(96.0%) (1.5%) (0.5%) (2.0%)
RT, Radiation therapy; tx, treatments.
Table II. Reason stated for referral for Mohs micrographic surgery Reason for referral
Recurrent tumor Tumor site Poorly defined tumor Tumor type Incomplete tumor excision Tumor size No details available
Primary BCC (N = 6252)
— 2490 (39.8%) 1982 (31.7%) 898 (14.4%) 603 (9.6%) 22 (0.4%) 257 (4.1%)
hence it is widely used for high-risk tumors and on the head and neck (recurrent or incompletely excised tumors, mid-facial location, [2 cm, aggressive histologic features, and deep and perineural invasion).9 The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia (SCFA) with the aim of collecting prospective data and involved all Mohs surgeons in the country. This first article describes all patients with BCC, treated with MMS, who were monitored by the SCFA between 1993 and 2002. The next two parts report the outcome in patients with 5-year follow-up (part 2) and the incidence, features, and outcomes of patients with perineural invasion (part 3).
METHOD We conducted a prospective, noncomparative, multicenter, interventional case series of patients with cutaneous BCC treated with MMS in Australia and monitored by the SCFA between 1993 and 2002. The selection criteria were all cases with histologically confirmed BCC and treated with MMS. The main data recorded were patient age and sex, reason for referral, duration of tumor, site, recurrences before MMS, preoperative tumor size, histologic classification of malignancy, number of excision levels, and postoperative defect size. Tumor and postoperative defect size were defined into 8 size 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 tumor extension
Previously recurrent BCC (N = 4875)
3681 253 454 148 162 1 176
(75.5%) (5.2%) (9.3%) (3.0%) (3.3%) (0.02%) (3.6%)
Overall (N = 11,127)
3681 2743 2436 1046 765 23 433
(33.1%) (24.6%) (21.9%) (9.4%) (6.9%) (0.2%) (3.9%)
is defined as the size difference between the clinical margin and the histologically clear margins. In our study, we defined the subclinical extension of the tumor as the difference in number of size groups between the defect and tumor size. All surgeons were 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 final histologic diagnosis was done on a debulking specimen before Mohs surgery or on the frozen sections seen on the routine Mohs surgical sections (or both), according to the surgeon’s preferences. In several centers, the final histologic specimens were also reviewed by an experienced dermatopathologist. Statistical analysis Associations between categorical variables were analyzed by means of x2 tests, with the MantelHaenszel test for linear association used where
Leibovitch et al 447
J AM ACAD DERMATOL VOLUME 53, NUMBER 3
Table III. Tumor age before excision in patients with basal cell carcinoma treated with Mohs micrographic surgery Tumor age* (y)
\1 1-5 5-10 [10 Data not available
Primary BCC (N = 6252)
2562 3122 119 44 405
(41.0%) (49.9%) (1.9%) (0.7%) (6.5%)
Previously recurrent BCC (N = 4875)
393 3005 934 334 209
(8.1%) (61.6%) (19.2%) (6.9%) (4.3%)
Overall (N = 11,127)
2955 6127 1053 378 614
(26.6%) (55.1%) (9.5%) (3.4%) (5.5%)
*P \ .001.
Table IV. Sites of basal cell carcinoma treated with Mohs micrographic surgery Site of BCC
Scalp Forehead Periocular region Auricular area Cheek and maxilla Nose Lips Chin and mandible Neck Upper limbs Trunk Genital Lower limbs Data not available
Primary tumors (N = 6252)
119 590 935 725 789 2540 295 85 90 18 35 2 7 27
(1.9%) (9.4%) (14.9%) (11.6%) (12.6%) (40.6%) (4.7%) (1.4%) (1.4%) (0.3%) (0.6%) (0.03%) (0.1%) (0.4%)
appropriate. Fisher’s exact test was used if expected values were less than 5. Comparison of normally distributed variables among groups was performed using t tests and analysis of variance; their nonparametric equivalent was used for non-normally distributed data. Analyses were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS The study group included 11,127 patients who underwent MMS for BCC between 1993 and 2002. There were 5231 female patients (47.1%) and 5886 male patients (52.9%) (P = .7), whose mean age was 62 6 14 years (median, 64 years; range, 15-98 years). In 6252 patients (56.2%), the lesion was a primary nonrecurrent tumor, and in 4875 patients (43.8%) the lesion was a recurrent tumor (previously treated with non-Mohs procedures; Table I). The most commonly stated reasons for patient referral for MMS was tumor recurrence (33.1%) and tumor site (24.6%) (Table II). Patients were mainly referred by a dermatologist (52.3%) or a general practitioner (37.7%). In most patients (6127 patients, 55.1%) the tumor age before excision ranged be-
Previously recurrent tumor (N = 4875)
64 410 483 543 1050 1806 183 42 140 25 87 1 10 26
(1.3%) (8.4%) (9.9%) (11.1%) (21.5%) (37.0%) (3.7%) (0.9%) (2.9%) (0.5%) (1.8%) (0.02%) (0.2%) (0.5%)
Overall (N = 11,127)
183 1000 1418 1268 1839 4346 478 127 230 43 122 3 17 53
(1.6%) (8.9%) (12.7%) (11.4%) (16.5%) (39.1%) (4.3%) (1.1%) (2.1%) (0.4%) (1.1%) (0.03%) (0.2%) (0.5%)
tween 1 and 5 years. As expected, previously recurrent tumors were present for a longer period (P \ .001; Table III). Most of the tumors were located on the head and neck (98.3%). The most common anatomic site for BCC was the nose (39.1%), followed by the cheek and maxilla (16.5%), periocular area (12.7%), and auricular region (11.4%). These were also the most common sites in each of the primary and recurrent BCC groups separately (Table IV). Tumor size before MMS was less than 2 cm in 8276 patients (74.4%); in 3358 patients it was less than 1 cm, and in 4918 patients it was between 1 and 1.9 cm (Table V). Previously recurrent tumors were larger than primary tumors (P \ .001). The postexcision defect size was less than 2 cm in 4667 patients only (41.9%), whereas in the majority of patients (58.1%), it was larger than 2 cm (Table VI). Defect sizes in previously recurrent tumors were larger than primary tumors (P \ .001). The subclinical tumor extension (the difference in number of size groups between the final postoperative defect and preoperative clinical tumor size) is presented in Table VII. Significant subclinical extension, defined
448 Leibovitch et al
J AM ACAD DERMATOL SEPTEMBER 2005
Table V. Preoperative tumor sizes in relation to prior recurrence in patients with basal cell carcinoma treated with Mohs micrographic surgery Tumor size* (cm)
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 Data not available
Primary BCC (N = 6252)
2331 2824 720 203 70 17 10 20 57
(37.3%) (45.2%) (11.5%) (3.2%) (1.1%) (0.3%) (0.2%) (0.3%) (0.9%)
Previously recurrent BCC (N = 4875)
1027 2094 959 338 165 48 20 63 161
(21.1%) (42.9%) (20.3%) (6.9%) (3.4%) (1.0%) (0.4%) (1.3%) (3.3%)
Overall (N = 11,127)
3358 4918 1679 541 235 65 30 83 218
(30.2%) (44.2%) (15.1%) (4.9%) (2.1%) (0.6%) (0.3%) (0.7%) (2.0%)
*P \ .001.
Table VI. Postoperative defect sizes in relation to prior recurrence in patients with basal cell carcinoma treated with Mohs micrographic surgery 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
Primary BCC (N = 6252)
348 2877 1740 736 256 115 62 23 11 84
(5.6%) (46.0%) (27.8%) (11.8%) (4.1%) (1.8%) (1.0%) (0.4%) (0.2%) (1.3%)
Previously recurrent BCC (N = 4875)
89 1353 1463 891 418 257 155 115 35 99
(1.8%) (27.7%) (30.0%) (18.3%) (8.6%) (5.3%) (3.2%) (2.4%) (0.7%) (2.0%)
Overall (N = 11,127)
437 4230 3203 1627 674 372 217 138 46 183
(3.9%) (38.0%) (28.8%) (14.6%) (6.1%) (3.3%) (1.9%) (1.2%) (0.4%) (1.6%)
*P \ .001.
as tumor defect exceeding tumor size by at least two size groups, was seen in 14.1% of primary tumors and in 26.7% of previously recurrent tumors (P \ .0001). The overall percentage of patients with significant subclinical extension was 20.3% (Table VII). Several anatomic sites (temple, auricular area, periocular area, nose, neck, and trunk) were also associated with a significant subclinical extension (P \.0001). The most common histologic subtypes of BCC were infiltrating (3417 patients, 30.7%), nodulocystic (2693 patients, 24.2%), and superficial (1510 patients, 13.6%). Similar proportions were noted in the primary and recurrent tumor groups (Table VIII). The morpheic subtype was more common in the female patients, whereas the basosquamous subtype was more common in the male patients (P \ .001). The infiltrating and morpheic histologic subtypes were associated with larger tumor and defect sizes, as well as significant subclinical extension (P \ .0001, P \ .0001, and P = .0006, respectively, for each of the subtypes). Perineural invasion
was diagnosed in 283 patients; 20 of them were treated with adjunctive radiation therapy. Data on perineural invasion are presented in part 3 of this study. The mean number of levels required for complete tumor excision was 1.73 (median, 2.0; range, 1-9 levels). Recurrent cases required more levels of excision (mean, 1.86; range, 1-9) compared with primary cases (mean, 1.63; range, 1-8) (P \ .001). Morpheic BCC and infiltrating BCC required more levels (mean, 2.04 and 1.98, respectively; P \.0001). Three thousand three hundred seventy patients (3370) completed a 5-year follow-up period. The data on these patients are presented in part 2 of this study.
DISCUSSION BCC is a common skin tumor, predominantly found on sun-exposed areas in fair-skinned persons.1,2 Although patients usually present with BCC in the fifth to eighth decades of life, the age range may be much wider, and there are reports of
Leibovitch et al 449
J AM ACAD DERMATOL VOLUME 53, NUMBER 3
Table VII. Subclinical extension (difference between tumor and defect sizes) in relation to previous recurrence of basal cell carcinoma Difference between tumor and defect size (number of size categories)
Primary BCC (N = 6074) Recurrent BCC (N = 4565) Total (N = 10,639)*
0
1
2
31
1835 (30.2%) 1153 (25.3%) 2988 (28.1%)
3380 (55.6%) 2193 (48.0%) 5573 (52.4%)
669 (11.0%) 805 (17.6%) 1474 (13.8%)
190 (3.1%) 414 (9.1%) 694 (6.5%)
0, Same size category for tumor and defect; 1, one size category difference between tumor and defect; 2, two size category difference between tumor and defect; 31, 3 or more size category difference between tumor and defect. *Data not available for 488 patients (4.4%).
Table VIII. Histologic subtypes of basal cell carcinoma treated with Mohs micrographic surgery Histologic subtype
Infiltrating Nodulocystic Superficial Morpheic Micronodular Basosquamous Combined subtypes Data not available
Primary BCC (N = 6252)
1848 1620 699 498 252 93 24 1218
(29.6%) (25.9%) (11.2%) (8.0%) (4.0%) (1.5%) (0.4%) (19.5%)
tumors occurring in the second decade of life.2,10,11 In most series there appears to be a male predominance.2,10,12,13 In our study, there were more male patients treated (52.9%) than female patients, but this was not statistically significant (P = .7). The mean age was 62 6 14 years (ranging between 15 and 98 years), similar to findings of previous reports. BCC is most commonly seen on the head and neck, mainly involving the central area of the face. In a large retrospective series by Scrivener, Grosshans, and Cribier10 of 13,457 patients with BCC at a dermatopathology referral center in France, 85% of the tumors were located on the head and neck. Bastiaens et al12 found that approximately 70% of cases occurred on the head and neck area in a series of patients in the Netherlands. Similar frequencies were reported by other authors reporting series from different geographical areas.2,14 Analysis of the anatomic distribution in our series showed that more than 98% of tumors were located on the head and neck, most commonly on the nose (39.1%), followed by the cheek and maxilla (16.5%), periocular area (12.7%), and auricular region (11.4%). Only 185 cases (1.7%) were found on other body areas. The predilection for the head and neck may be explained by higher sun exposure. In our series, there may also be a referral bias for treatment with Mohs surgery for mid-facial BCCs as they are higher risk tumors.4
Previously recurrent BCC (N = 4875)
1569 1073 811 359 227 85 37 714
(32.2%) (22.0%) (16.6%) (7.4%) (4.7%) (1.7%) (0.8%) (14.6%)
Overall (N = 11,127)
3417 2693 1510 857 479 178 61 1932
(30.7%) (24.2%) (13.6%) (7.7%) (4.3%) (1.6%) (0.5%) (17.4%)
The clinical and histologic presentations of BCC are varied. Clinically, it is usually slowly progressive, presenting as a papule, nodule, plaque, ulcer (‘‘rodent ulcer’’) or cyst. The color is usually red to white but may be blue-black. There is a characteristic ‘‘pearly’’ translucence to most lesions when placed on the stretch and overlying telangiectases are common.2 A small percentage of lesions aggressively invade deeper tissues and some rare cases metastasize.2,4 Histologically, BCC is composed of islands or nests of basaloid cells with peripheral palisading and frequent mitotic figures. Several subtypes of BCC have clinical importance.2,4,15 The nodular type is the most common and least invasive, accounting for 70% of cases. It shows typical peripheral palisading and includes a nodulocystic variant with central mucin accumulation. The micronodular subtype is composed of small round tumor islands and has a greater propensity for subclinical extension and local recurrence.2 The superficial subtype is less aggressive and accounts for 10% to 15% of cases. It exhibits an irregular proliferation of tumor cells attached to an atrophic epidermis with almost no penetration to the dermis.12 The least common but more aggressive subtypes are morpheic, infiltrating, and basosquamous; together they account for 15% of cases.2,4 The morpheic subtype shows strands of atypical basaloid cells embedded in a dense fibrous stroma, whereas
450 Leibovitch et al
J AM ACAD DERMATOL SEPTEMBER 2005
in the infiltrating type these cell strands are only a few layers thick and with almost no peripheral palisading.12 The basosquamous variant is characterized by areas of BCC with typical basaloid cells and areas of squamous cell carcinoma differentiation, having a transition zone with intermediate cells in between.2 In our study, the most common histologic subtypes of BCC were infiltrating (30.7%), nodulocystic (24.2%), and superficial (13.6%) (Table VIII). Overall, the 3 more aggressive subtypes (morpheic, infiltrating and basosquamous) accounted for 40% of cases, which is much higher than the 15% commonly cited in the literature.2 This relatively high proportion of aggressive subtypes is undoubtedly influenced by referral bias for MMS. As demonstrated in Table II, more than 30% of cases were referred to MMS because of tumor histology or a poorly defined lesion, which is more common with these subtypes and may explain their relative preponderance. We also found that the infiltrating and morpheic histologic subtypes were associated with larger tumor size, defect size, as well as significant subclinical extension (P \ .0001, P \ .0001, and P = .0006, respectively, for each of the subtypes). In addition, these two subtypes of BCC required more Mohs levels (P\.0001). Batra and Kelley16 described 868 patients with BCC and found that morpheic tumors were 2.3 times (P \.001) as likely to exhibit extensive subclinical extension compared with primary nodular BCC. These findings emphasize the increased local invasiveness of these histologic subtypes. There were 4874 patients in our series with recurrent tumors, all of whom had been treated previously with modalities other than MMS (Table I). Previously recurrent tumors were larger than primary tumors (P \ .001), required more levels of excision (P \.001), and the postexcision defect sizes were larger (P \.001). Significant extension, defined as tumor defect exceeding tumor size by at least two size groups, was seen in 14.1% of primary tumors and in 26.7% of previously recurrent tumors (P \ .0001). That recurrent tumors are associated with significant subclinical extension has been shown in previous studies. Batra and Kelley16 found that recurrent tumors were 3.2 times (P \ 0.001) as likely to exhibit extensive subclinical extension compared with primary BCC. They also found that larger tumors were associated with more extensive subclinical extension. The significant subclinical extension in our series further emphasizes the importance of margin-controlled excision for BCC and may explain the failure rate in some of the non-MMS treatment modalities, which are based solely on clinical margins with no histologic control. Furthermore,
previously recurrent lesions treated with destructive modalities such as cryotherapy may have architectural changes that make margin-control excision very difficult. Recurrent or incompletely excised tumors are contributing factors to more aggressive behavior of BCC.4 Lang and Maize17 reported that 65% of recurrent BCCs demonstrated aggressive histologic subtypes. It has been postulated by Richmond and Devie18 that incomplete excision may also contribute to the evolution of an aggressive BCC phenotype in part due to the presence of scar tissue, which obscures monitoring and delays clinical detection of recurrence. In addition, the fibrosis may entrap malignant cells and favor deep extension by preventing upward migration. It is also possible that tumors with more aggressive histologic subtypes are more likely to be incompletely excised particularly when unmonitored excision is used. These findings further emphasize the importance of early detection of BCC and treatment with margin control to reduce the risk of recurrence. In conclusion, this study is the largest reported prospective nationwide series of BCC managed by MMS. This series is characterized by a high percentage of head and neck cases as well as recurrent cases. In addition, a significant number of patients had large tumors. These factors contribute to a more aggressive nature and define BCCs as high-risk tumors.5 The most common histologic subtypes were infiltrating and nodulocystic BCC. The nose, cheek and maxilla, periocular area, and auricular region were most commonly affected. Previously recurrent tumors were larger than primary tumors, had a larger postexcision defect, a more extensive subclinical extension, and required more levels of excision. We thank the Skin and Cancer Foundation Australia and 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. Wong CSM, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003;327:794-8. 2. Weedon D. Tumors of the epidermis. In: Skin pathology. London: Churchill-Livingstone; 1997. pp. 648-51. 3. Miller SJ. Biology of basal cell carcinoma (Part I). J Am Acad Dermatol 1991;24:1-13.
J AM ACAD DERMATOL
Leibovitch et al 451
VOLUME 53, NUMBER 3
4. Walling HW, Fosko SW, Geraminejad PA, Whitaker DC. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev 2004;23:389-402. 5. 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. 6. Marks R, Staples M, Giles G. Trends in non-melanocytic skin cancer treated in Australia: the second national survey. Int J Cancer 1993;53:585-90. 7. Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population. Int J Cancer 1990; 46:356-61. 8. Netscher DT, Spira M. Basal cell carcinoma: an overview of tumor biology and treatment. Plast Reconstr Surg 2004; 113:74e-94e. 9. Shriner DL, McCoy DK, Goldberg DJ, Wagner RF Jr. Mohs micrographic surgery. J Am Acad Dermatol 1998;39:79-97. 10. Scrivener Y, Grosshans E, Cribier B. Variations of basal cell carcinomas according to gender, age, location and histopathological subtype. Br J Dermatol 2002;147:41-7. 11. Rahbari H, Mehregan AH. Basal cell epithelioma (carcinoma) in children and teenagers. Cancer 1982;49:350-3.
12. Bastiaens MT, Hoefnagel JJ, Bruijn JA, Westendorp RG, Vermeer BJ, Bouwes Bavinck JN. Differences in age, site distribution and sex between nodular and superficial basal cell carcinomas indicate different type of tumors. J Invest Dermatol 1998;110:880-4. 13. Tran H, Chen K, Shumack S. Epidemiology and aetiology of basal cell carcinoma. Br J Dermatol 2003;149:50-2. 14. Kopf AW. Computer analysis of 3531 basal cell carcinomas of the skin. J Dermatol 1979;6:267-81. 15. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol 1990; 23:1118-26. 16. Batra RS, Kelley LC. Predictors of extensive subclinical spread in nonmelanoma skin cancer treated with Mohs micrographic surgery. Arch Dermatol 2002;138:1043-51. 17. Lang PG Jr, Maize JC. Histologic evolution of recurrent basal cell carcinoma and treatment implications. J Am Acad Dermatol 1986;14:186-96. 18. Richmond J, Devie RM. The significance of incomplete excision in patients with basal cell carcinoma. Br J Plast Surg 1987; 40:63-7.