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Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years
DERMATOLOGIC
SURGERY
Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years Igal Leibovitch, MD,a Shyamala C. Huilgol, FACD,b,d Dinesh Selva, FRANZCO,a,c Dudley Hill, FACD,d Shawn Richards, FACD,e and Robert Paver, FACDe Adelaide, South Australia, and Sydney, Australia Background: Only a few reports have been published on the long-term outcome of surgical excision of cutaneous squamous cell carcinoma (SCC). Objective: Our purpose was to report the clinical findings and 5-year recurrence rate of all patients with cutaneous SCC treated with Mohs micrographic surgery (MMS) in Australia between 1993 and 2002. Method: This prospective, multicenter case series included all patients with SCC who were monitored by the Skin and Cancer Foundation. The main outcome measures were patient demographics, reason for referral, duration of tumor, site, preoperative tumor size, postoperative defect size, recurrences before MMS, histological subtypes, and 5-year recurrence after MMS. Results: The case series comprised 1263 patients (25.7% female and 74.3% male; P \ .0001) with a mean age of 66 6 13 years. In 61.1% of cases the lesion was a primary tumor, and in 38.9% it was a recurrent tumor. Most of the tumors (96.5%) were on the head and neck area. Recurrent tumors were larger than primary tumors (P \.0001), had a larger postexcision defect (P \.0001), required more levels of excision (P \.0001), and had more cases of subclinical extension (P = .002). Recurrence after MMS was diagnosed in 15 of the 381 patients (3.9%) who completed the 5-year follow-up after MMS. The recurrence rate was 2.6% in patients with primary SCC and 5.9% in patients with previously recurrent SCC (P \ .001). Conclusion: This large prospective series of SCC managed by MMS is characterized by a high percentage of high-risk tumors. The low 5-year recurrence rate with MMS emphasizes the importance of margincontrolled excision. ( J Am Acad Dermatol 2005;53:253-60.)
S
quamous cell carcinoma (SCC) is the second most common skin malignancy after basal cell carcinoma (BCC) in fair-skinned persons.1,2 Reports indicate a significant rise in the incidence of SCC over the past two decades,3,4 and it is estimated that the age-adjusted annual incidence of SCC among white persons in the United States and Canada is 100 to 150 per 100,000 persons.4 In
From the Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences,a the Department of Dermatology,b and the Department of Surgery,c Royal Adelaide Hospital, University of Adelaide; Wakefield Clinic, Adelaided; and Skin and Cancer Foundation Australia, Sydney.e Funding sources: None. Conflicts of interest: None disclosed. Reprint requests: Dr Shyamala Huilgol, Wakefield Clinic, 270 Wakefield St, Adelaide SA 5000. E-mail: [email protected]. sa.gov.au. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.02.059
Australia the estimated annual incidence rate was 321 per 100,000 persons 14 years of age and older in 1995, with a significant latitude gradient, resulting in an incidence of more than 1000 per 100,000 in some northern parts of Australia.5,6 SCC most often arises in areas of direct sun exposure, with a marked predilection for the head and neck.2,4,7-9 These tumors are usually progressively enlarging, but some follow a more aggressive course, are rapidly invasive, and carry a high risk of metastasis.4,7 Treatment modalities for SCC include surgery and other techniques.10 Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation; hence it is useful for high-risk tumors (recurrent or incompletely excised tumors, mid-facial location, size larger than 2 cm, aggressive histologic changes, and perineural invasion).9-11 The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia (SCFA) with the aim of collecting prospective 253
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Table I. Prior treatments for recurrent squamous cell carcinoma Prior treatments (No. of patients) No. of tx
1 2 3 $4
Cryotherapy (n = 294)
123 91 28 52
(41.8%) (30.9%) (9.5%) (17.7%)
Curettage and cautery (n = 86)
74 (86%) 12 (14.0%) — —
Surgical excision (n = 265)
220 38 6 1
(83%) (14.3%) (2.3%) (0.4%)
RT (n = 17)
16 (94.1%) 1 (5.9%) — —
RT, Radiation therapy; tx, treatments.
data and involved all Mohs surgeons in the country. This first article reports all patients with cutaneous SCC, treated with MMS, who were monitored by the SCFA between 1993 and 2002 and the outcome in patients with a 5-year follow-up. The second part will report the incidence, features, and outcomes of patients with perineural invasion.
METHODS We conducted a prospective, noncomparative, multicenter, interventional case series of patients with cutaneous SCC treated with MMS in Australia and monitored by the SCFA between 1993 and 2002. The selection criteria were all cases with histologically confirmed SCC and treated with MMS. The main data recorded were patient age and gender, reason for referral, duration of tumor, site, recurrences before MMS, preoperative tumor size, histological subtypes and evidence of perineural invasion, number of excision levels, postoperative defect size, and recurrence at 5-years after MMS. 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 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 the number of size groups between the defect and tumor size. All surgeons used a standard fresh-frozen MMS technique with a tissue map and 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 frozensection preparation. Residual tumor was mapped and targeted serial excision performed until the surgical margins were clear. All excision, mapping, and tissue examination was 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. Excision margins for initial and subsequent layers varied according to tumor and site and between different surgeons. Statistical analysis Associations between categorical variables were analyzed by x2 tests, with the Mantel-Haenszel 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 using t tests and analysis of variance; their nonparametric equivalent was used for non-normally distributed data. Analyses were performed using SAS Version 9.1 (SAS Institute Inc., Cary, NC).
RESULTS Patients treated with MMS The study group included 1263 patients who underwent MMS for cutaneous SCC between 1993 and 2002. There were 324 women (25.7%) and 938 men (74.3%) (P \.0001), with a mean age of 66 6 13 years (median, 68 years; range, 21-96 years). In 772 patients (61.1%) the lesion was a primary tumor, and in 491 patients (38.9%) the tumor was recurrent (previously treated with non-Mohs procedures; Table I). The most commonly stated reasons for referral for MMS was tumor site (24.4%) and tumor recurrence (24.1%) (Table II). Patients were mainly referred by a dermatologist (48.3%) or a general practitioner (31.2%). In most patients (657 patients, 52.0%) the tumor age before excision was less than 1 year. As expected, recurrent tumors were present for a longer period than primary tumors (P \.0001; Table III). The majority of tumors were located on the head and neck (96.5%). The most common anatomic sites were the nose (20.0%), cheek and maxilla (19.8%), and auricular region (18.2%). These were also the most common sites in each of the primary and recurrent groups separately (Table IV). Tumor size was less than 2 cm in 838 patients (66.3%); in 273 patients it was less than 1 cm, and in 565 patients it was between 1 and 1.9 cm (Table V).
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Table II. Reason stated for referral for Mohs micrographic surgery Reason for referral
Primary SCC (N = 772)
Tumor site Recurrent tumor Poorly defined tumor Tumor type Incomplete tumor excision Tumor size No details available
238 (30.8%) — 209 (27.1%) 128 (16.6%) 106 (13.7%) 4 (0.5%) 69 (8.9%)
Table III. Tumor age before excision in patients with squamous cell carcinoma treated with Mohs micrographic surgery Tumor age* (y)
Primary SCC (N = 772)
\1 1-5 5-10 [10 NA
527 200 11 5 29
(68.3%) (25.9%) (1.4%) (0.6%) (3.8%)
Previously recurrent SCC (N = 491)
130 274 58 13 16
(26.5%) (55.8%) (11.8%) (2.6%) (3.3%)
Overall (N = 1263)
657 474 69 18 45
(52.0%) (37.5%) (5.5%) (1.4%) (3.6%)
NA, Data not available; SCC, squamous cell carcinoma. *P \ .0001.
Recurrent tumors were significantly larger than primary tumors (P \.0001). The postexcision defect size was less than 2 cm in 428 patients (33.9%), whereas in the majority of patients (66.1%) it was larger than 2 cm (Table VI). Defect sizes in recurrent tumors were larger than primary tumors (P \.0001). Significant subclinical extension, defined as tumor defect exceeding tumor size by at least 2 size groups, was seen in 15.3% of primary tumors and in 23.1% of recurrent tumors (P = .002). The overall percentage of patients with significant subclinical extension was 18.2%. Several anatomic sites (scalp, auricular area, periocular area, nose) were also associated with a significant subclinical extension (P \.0001). The most common histological subtypes were moderately differentiated (444 patients, 35.1%) and well differentiated (440 patients, 34.8%). The poorly differentiated and acantholytic subtypes were less common and were found to be associated with previous recurrence (P = .02; Table VII). Female gender was associated with a moderately differentiated or well-differentiated SCC, whereas male gender was associated with a poorly differentiated or acantholytic SCC (P = .002). The poorly differentiated or acantholytic subtypes were also associated with larger tumor and defect sizes (P \.001), as well as significant subclinical extension (P = .005). Perineural invasion (PNI) was diagnosed in 70 patients, and the data will be presented in part 2 of this study.
Previously recurrent SCC (N = 491)
70 304 56 22 20 3 14
(14.3%) (61.9%) (11.4%) (4.5%) (4.1%) (0.6%) (2.8%)
Overall (N = 1263)
308 304 285 150 126 7 83
(24.4%) (24.1%) (22.6%) (11.9%) (10.0%) (0.5%) (6.6%)
The mean number of levels required for complete tumor excision was 1.60 (median, 1.0; range, 1-7 levels). Recurrent cases required more levels of excision (mean, 1.73; range, 1-6) compared with primary cases (mean, 1.54; range, 1-7) (P \ .0001). The poorly differentiated and acantholytic subtypes also required more levels (mean, 1.86 and 1.82, respectively; P \ .001). It was also found that men required more excision levels than women (1.74 6 0.8 vs 1.4 6 0.7; P \.001). Forty-five patients (3.6%) were treated with adjunctive local radiation therapy after MMS, 37 of whom had PNI. Patients with 5-year follow-up Three hundred eighty-one patients (100 women and 281 men) who completed 5-year follow-up after MMS. The mean age of these patients was 65 6 13 years (median, 66; range, 21-96 years). In 229 patients (60.0%) the lesion was a primary tumor, and in 152 (40.0%) the tumor was recurrent (previously treated with non-Mohs procedures). Most of the tumors were located on the head and neck (96.3%). The most common site was the nose (85 patients, 22.3%), followed by the auricular region (70 patients, 18.4%), cheek and maxilla (69 patients, 18.1%), and the periocular area (39 patients, 10.2%). Tumor size was less than 2 cm in 261 patients (68.5%), less than 1 cm in 86, and between 1 and 1.9 cm in 175. The defect was less than 2 cm in 143 patients (37.5%), whereas in the majority (62.5%) it was larger than 2 cm. The percentage of patients with significant subclinical extension (defined as the defect exceeding tumor size by at least 2 size groups) was 18.6%. The mean number of Mohs stages required for tumor removal was 1.6 6 0.8 (median, 1.0; range, 1-5). The most common histological subtypes were well differentiated and moderately differentiated (44.4% and 36.0%, respectively). The acantholytic and poorly differentiated subtypes comprised 13.5% and 6.4% of cases, respectively. Twenty-five patients with PNI completed a 5-year follow-up period, and these data will be presented in part 2 of this study.
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Table IV. Sites of squamous cell carcinoma treated with Mohs micrographic surgery Site of SCC
Scalp Forehead Periocular area Auricular area Cheek and maxilla Nose Lips Chin and mandible Neck Upper limbs Trunk Genitalia Lower limbs NA
Primary SCC (N = 772)
70 67 73 141 145 147 80 5 16 14 3 1 7 3
(9.1%) (8.7%) (9.5%) (18.3%) (18.8%) (19.0%) (10.4%) (0.6%) (2.1%) (1.8%) (0.4%) (0.1%) (0.9%) (0.4%)
Previously recurrent SCC (N = 491)
43 40 40 89 105 105 28 6 13 9 5
(8.8%) (8.1%) (8.1%) (18.1%) (21.4%) (21.4%) (5.7%) (1.2%) (2.6%) (1.8%) (1.0%) — 5 (1.0%) 3 (0.6%)
Overall (N = 1263)
113 107 113 230 250 252 108 11 29 23 8 1 12 6
(8.9%) (8.5%) (8.9%) (18.2%) (19.8%) (20.0%) (8.6%) (0.9%) (2.3%) (1.8%) (0.6%) (0.1%) (0.9%) (0.5%)
NA, Data not available; SCC, squamous cell carcinoma.
Five-year follow-up data were not available for 882 patients. We compared the parameters of these patients with those who had 5-year follow-up data to identify differences between the two groups. No significant differences between the two groups were identified for age (P = .8), gender (P = .7), tumor age (P = .2), tumor site (P = .2), percentage of previously recurrent cases (P = .4), tumor and defect size (P = .6 and P = .4, respectively), histological subtypes (P = .5), and number of Mohs stages (P = .7). Five-year recurrence data Recurrence at 5-year follow-up after MMS was documented in 15 of 381 patients (3.9%; exact 95% confidence interval [CI], 2.2%-6.4%). There were 6 cases of recurrence at 5 years in the 229 patients with primary SCC (2.6%; exact 95% CI, 1.0%-5.7%), and 9 cases of recurrence in the 152 cases with previously recurrent tumors (5.9%; exact 95% CI, 3.0%-11.9%) (P \ .001) (Table VIII). Two of the cases with recurrence at 5 years were initially treated with adjunctive radiation therapy after MMS. The 15 patients with recurrence at 5 years included 11 men (73.3%) and 4 women (26.7%). The most common site for recurrence was the nose (33.3% of cases) followed by the auricular area (20.0%) and forehead (20.0%). No association was found between tumor site, histological subtypes, tumor size at presentation or postexcision defect, and recurrence at 5 years (P = .4, P = .3, P = .7 and P = .4, respectively). Significant subclinical extension was evident in 4 cases (26.7%) (P = .07). The mean number of levels required in patients with recurrence at 5 years was 2.2 (median, 2.0; range, 1-4 levels), whereas in patients with no recurrence at
5 years it was 1.70 (median, 2.0; range 1-5 levels) (P = .01). No cases of metastatic disease were documented in patients who were initially treated with MMS or in those who completed the 5-year follow-up period.
DISCUSSION The significant increase in the incidence of nonmelanoma skin cancers (NMSCs) over the past two decades has resulted in a growing number of studies on epidemiology, risk factors, and treatment modalities. SCC, which constitutes 20% to 25% of NMSC, is mainly associated with ultraviolet radiation, but other possible risk factors are ionizing radiation, chemical agents (arsenic, polycyclic aromatic hydrocarbons, smoking), genodermatoses (albinism and xeroderma pigmentosum), human papillomavirus infection, immunosuppression, and chronically injured skin (ulcers, burns, sinus tracts, vaccination scars, and chronic skin diseases).4,7-9,12 SCC occurs predominantly in older patients in their seventh decade, but the age range may be much wider; there are rare reports of tumors occurring in the second decade.13 In most series there appears to be a male predominance. In a recent report, Diepgen and Mahler12 reviewed a large number of series from the United States, Europe, and Australia and showed that the male/female ratio in most series of SCC was 2-3:1. A similar male/female ratio (3:1) was found in our study, and the mean age was 66 6 13 years (ranging between 21 and 96 years), correlating with previous reports. SCC is most commonly seen on areas of direct exposure to sun, mainly the head and neck area, upper limbs, and trunk. Analysis of the anatomic distribution in our series showed that more than 96%
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Table V. Preoperative tumor sizes in relation to prior recurrence in patients with squamous cell carcinoma treated with Mohs micrographic surgery
Table VI. Postoperative defect sizes in relation to prior recurrence in patients with squamous cell carcinoma treated with Mohs micrographic surgery
Tumor size* (cm)
Primary SCC (N = 772)
Defect size* (cm)
Primary SCC (N = 772)
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 NA
198 357 119 51 18 8 4 1 16
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 [10 NA
32 273 251 98 62 18 12 9 1 16
(25.6%) (46.2%) (15.4%) (6.6%) (2.3%) (1.0%) (0.5%) (0.1%) (2.1%)
Previously recurrent SCC (N = 491)
75 208 118 31 23 10 4 2 20
(15.3%) (42.4%) (24.0%) (6.3%) (4.7%) (2.0%) (0.8%) (0.4%) (4.1%)
Overall (N = 1263)
273 565 237 82 41 18 8 3 36
(21.6%) (44.7%) (18.7%) (6.5%) (3.2%) (1.4%) (0.6%) (0.2%) (2.8%)
NA, Data not available; SCC, squamous cell carcinoma. *P \ .0001.
of tumors were located on the head and neck, most commonly on the nose (20.0%), cheek and maxilla (19.8%), and auricular region (18.2%). Only 3.5% were found on other body areas. Although the predilection for the head and neck may be partly explained by higher sun exposure, there is most likely a strong referral bias in our series for treatment of lesions in these areas with Mohs surgery.14 Histologically, SCC is composed of nests of squamous epithelial cells that arise from epidermis and invade the dermis. The degree of anaplasia in the tumor nests is used to grade SCC, based on a subjective assessment of differentiation.7 The categories are ‘‘well’’ differentiated (the relative proportion of anaplastic cells is low, and the architecture resembles normal epidermis), ‘‘moderately’’ differentiated (half of the cells or more are anaplastic), and ‘‘poorly’’ differentiated (all cells are anaplastic, and diagnosis is based on keratin markers). The acantholytic variant, which is more common on the head and neck, accounts for only 2% to 4% of all SCC cases.7 It consists of nests of squamous cells with central acantholysis leading to an impression of gland formation and is considered more aggressive.7 The most common histological subtypes in our study were the moderately differentiated (35.1%) and well differentiated (34.8%) (Table VII). The more aggressive subtypes (poorly differentiated and acantholytic) constituted 20% of cases, which is higher than their general proportion in SCC cases.7 This relatively high proportion of aggressive subtypes is undoubtedly influenced by referral bias for MMS. As demonstrated in Table II, almost 35% of cases were referred to Mohs surgery because of tumor histology or a poorly defined lesion, which is more common with these subtypes, and may explain their relative pre-
(4.1%) (35.4%) (31.2%) (12.7%) (8.0%) (2.3%) (1.6%) (1.2%) (0.1%) (2.1%)
Previously recurrent SCC (N = 491)
6 117 157 100 41 29 20 7 2 12
(1.2%) (23.8%) (32.0%) (20.4%) (8.3%) (5.9%) (4.1%) (1.4%) (0.4%) (2.4%)
Overall (N = 1263)
38 390 408 198 103 47 32 16 3 28
(3.0%) (30.9%) (32.3%) (15.7%) (8.2%) (3.7%) (2.5%) (1.3%) (0.2%) (2.2%)
NA, Data not available; SCC, squamous cell carcinoma. *P \ .0001.
ponderance. Not surprisingly, less-differentiated histology was associated with previous recurrence (P = .02), larger tumor and defect sizes (P \ .001), significant subclinical extension (P = .005), as well as more levels of excision (P\.001). Similar findings, which emphasize the importance of tumor excision with margin control, were reported by Brodland and Zitelli,15 who studied a group of 141 primary tumors. They concluded that a 6-mm margin was required to clear 95% of high-risk tumors ([2 cm, periocular location, and poor histologic differentiation), compared with only 4 mm for low-risk SCC. Four hundred ninety-one patients (38.9%) in our series had recurrent tumors, all of whom had been treated previously with modalities other than MMS (Table I). These recurrent tumors were larger than primary tumors (P \.0001), required more levels of excision (P \ 0.0001), and had larger postexcision defect sizes (P \ .0001). Significant subclinical extension, defined as tumor defect exceeding tumor size by at least 2 size groups, was seen in 15.3% of primary tumors and 23.1% of recurrent tumors (P = .002). The significant subclinical extension in our series further emphasizes the importance of margin-controlled excision for SCC and may explain the failure rate in those treatment modalities based solely on clinical margins (eg, radiation therapy) with no histological control. Furthermore, recurrent lesions treated with destructive modalities such as cryotherapy may have architectural changes that obscure monitoring, delay clinical detection of recurrence, and make later margin-controlled excision more difficult. In addition, the fibrosis may entrap malignant cells, favor deep extension by preventing upward migration, and, again, delay clinical detection.
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Table VII. Histologic subtypes of squamous cell carcinoma treated with Mohs micrographic surgery Histologic subtype
Primary SCC (N = 772)
Well differentiated Moderately differentiated Poorly differentiated* Acantholytic* NA
269 281 46 80 96
(34.8%) (36.4%) (6.0%) (10.4%) (12.4%)
Previously recurrent SCC (N = 491)
171 163 51 76 30
(34.8%) (33.2%) (10.4%) (15.5%) (6.1%)
Overall (N = 1263)
440 444 97 156 128
(34.8%) (35.1%) (7.7%) (12.3%) (10.1%)
NA, Data not available; SCC, squamous cell carcinoma. *P = .02.
Table VIII. Five-year recurrence rate after Mohs micrographic surgery in relation to previous recurrence of squamous cell carcinoma 5-year recurrence
Yes No %*
Primary SCC (N = 229)
Previously recurrent SCC (N = 152)
Overall patients with 5 years follow-up (N = 381)
6 223 2.6
9 143 5.9
15 366 3.9
*P \ .001.
The choice of treatment options for cutaneous SCC is based on variables such as patient factors (age, sex, general health), tumor characteristics (size, location, histologic subtype), as well as the treating physician’s and patient’s preference and available resources.8 Nonsurgical treatments used for SCC include cryotherapy and radiation therapy. Cryotherapy, using liquid nitrogen, is generally used to treat only small and well-defined low risk tumors, where it was reported to achieve short-term recurrence rates as low as 3%.10,14,16 This treatment modality is generally contraindicated in high-risk tumors, such as recurrent, large, and mid-facial SCC, with aggressive histology.14 Radiation therapy is a preferred treatment modality in older and disabled patients with large tumors, when surgical treatment may not be appropriate.4,14 This treatment is relatively contraindicated in cases with ill-defined clinical tumor margins.14 Rowe, Carroll, and Day10 reviewed all studies since 1940 on the prognosis and treatment of cutaneous SCC. They found that in 633 cases of primary SCC, with less than 5 years follow-up, the recurrence rate with radiation therapy was 6.7%, whereas in 160 patients, with at least 5 years of follow-up, the recurrence rate was 10%. The recurrence rate with radiotherapy for more advanced stages of primary tumors and for previously recurrent tumors reached 35% to 50%.17 In a recent report by Kwan, Wilson, and Moravan18 the 4-year recurrence rate for locally advanced SCC was as high as
42%, occurring very early after treatment (median 5 months). Radiation therapy is also used as adjunctive postsurgical treatment of high-risk tumors with perineural invasion and positive surgical margins and in the control of metastatic disease.9 Forty-five patients in our series (3.6%) were treated with postsurgical radiation therapy, mainly in cases with PNI. This aspect in the treatment of SCC with PNI is further discussed in part 2 of our report. Curettage and cautery is also reported to have excellent cure rates in SCC, but once again, this is based on series reporting the outcome for low-risk tumors.14 Rowe, Carroll, and Day10 calculated a 5-year recurrence rate of 3.7% in primary tumors, previously reported in other series. Surgical excision is the most frequent treatment modality for SCC and is considered the treatment of choice for most tumors. Excision without margin control is estimated to have a 5-year recurrence rate of 5% to 18.7% for primary tumors in different locations10,14,15 and more than 23% for previously recurrent SCC.10 In a review of 1006 patients with primary SCC treated with surgical excision and followed up for less than 5 years, Rowe, Carroll, and Day10 calculated a 5-year recurrence rate of 5.7%, whereas in 124 patients with 5 years or more of follow-up, the recurrence was 8.1%. They also found a 5-year recurrence rate of 23.3% in 34 patients with previously recurrent tumors treated with surgical excision. 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.19 For that reason, it is generally accepted that MMS is indicated in high-risk tumors.8,11,14 A few large-scale studies have previously evaluated the role of MMS in treating cutaneous SCC (Table IX). Our study, which is based on the Australian MMS database, is one of the largest reported prospective nationwide series of patients
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Table IX. Comparative clinical and 5-year recurrence data on Mohs micrographic surgery for squamous cell carcinoma Mohs20,21
Study years Tumor location Overall number of tumors with 5-y follow-up (18/28) Overall 5-y recurrence (%) (18/28)
Robins et al22,23
Holmkvist & Roenigk*
Our study
NA Head 2551 (NA)
1965-1980 Head 414 (18)
1986-1989 Lips 50 (NA)
1993-2002 Mainly head and neck 381 (229/152)
5.6 (NA)
6.7 (1.8/3.4)
8.0 (NA)
3.9 (2.6/5.9)
18, Primary; 28, recurrent; NA, not available. *Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years. J Am Acad Dermatol 1998;38:960-6.
with SCC managed by MMS. This series is characterized by a high percentage of high-risk head and neck tumors. The 5-year recurrence rate in primary cases was 2.6%, whereas in previously recurrent cases it was 5.9%. The overall 5-year recurrence rate for all 381 patients who completed the follow-up period was 3.9%. These recurrence rates are low, particularly in view of the significant number of high-risk tumors included. The largest series of patients with SCC, treated with MMS and followed up for a period of 5 years, was reported by Mohs.20,21 He found an overall 5-year recurrence rate of 5.6% in a series of 2551 patients with SCC. Robins, Dzubow, and Rigel22 and Dzubow, Rigel, and Robins23 reported similar 5-year recurrence rates (6.7%) in a series of 414 patients with primary SCC treated with MMS. In their retrospective literature review of treatment modalities for SCC since 1940, Rowe, Carroll, and Day10 found that the 5-year recurrence rate for 2065 cases of primary SCC treated with MMS was 3.1%, whereas for 151 previously recurrent cases it was 10.0%. MMS was also shown to provide the highest cure rates for larger tumors ([2 cm), as well as those with poorly differentiated histologic features, compared with other treatments. They concluded that all non-Mohs treatment modalities achieve similar cure rates, but MMS offered the best cure rates with the lowest recurrence rates and should be considered the treatment of choice for high-risk SCC. Several factors have been found to correlate with a higher risk of recurrence and metastasis of SCC. Tumors larger than 2 cm in diameter are twice as likely to recur locally (15.2% vs 7.4%) and 3 times as likely to metastasize (30.3% vs 9.1%) as tumors smaller than 2 cm.10,14 Tumor depth greater than 4 mm (Clark level IV) is associated with an increased risk of metastasis compared with more superficial lesions (45.7% and 6.7%, respectively).10,14 Tumor location in previous areas treated by radiation, thermal injury, Bowen’s disease, chronic ulcers, as well as specific sites such as the ear, lips, and genital area, were also found to be associated with a higher risk of
recurrence and metastasis.9,10,14 Tumors with poor histologic differentiation (as well as acantholytic features and PNI) are associated with a higher recurrence and metastatic rate compared with welldifferentiated tumors (28.6% vs 13.6% and 32.8% vs 9.2%, respectively).7,10,14 Locally recurrent SCCs have a higher risk (25%-45%) of further recurrence and metastasis after secondary treatment.9,10 Another important factor is the immune status of the patient; immunocompromised patients are at increased risk for recurrence and metastatic lesions.10 Recent studies show that SCC is up to 65 times as likely to develop in transplant recipients as in age-matched controls.24 In our study we documented tumor factors such as size, location, histology, and previous recurrence, but data on tumor depth, previous skin disease, and the immune status of the patient were not available. The main predictors for recurrence in our study were previous recurrence, significant subclinical extension, and more Mohs levels (P \ .001, P = .07, and P = .01, respectively). We found no association between tumor site, histological subtype, tumor size at presentation, or postexcision defect and recurrence at 5 years. Although MMS provides the highest cure rate for high-risk SCC, there were still recurrences in our series, especially in previously recurrent tumors. The causative factors include technical difficulties and errors during Mohs surgery; the selection of a more aggressive group of tumors; and the presence of discontinuous tumor and ‘‘skip’’ lesions, resulting from previous treatment, which make margincontrolled excision more difficult. For this reason, Mohs surgeons will usually remove the entire scar from previous treatment as well as the recurrent tumor and then evaluate the margins of the surrounding tissue.9,25 Although Mohs surgery serves as a method for complete tumor removal with normal tissue conservation, there are Mohs surgeons who apply the narrowest margins possible even for higher risk tumors, and this may result in lower cure rates. The data on excisional margins that were
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used by Mohs surgeons in our series were not recorded; therefore the role of this variable in tumor recurrence could not be analyzed. Only 30.2% of the patients in our series (381/1263), who were initially treated with MMS, completed the 5-year follow-up period. Although these missing data are certainly important, we found no significant differences between the patients who completed the follow-up and those who did not, and we believe that the information obtained after 5 years gives a valuable estimation of the cure rate for highrisk SCC. In conclusion, this study is the largest reported prospective nationwide series of SCC managed by MMS. This series is characterized by a high percentage of poorly differentiated large head and neck tumors, as well as recurrent cases. These factors contribute to a more aggressive nature and define them as high risk tumors. The relatively low 5-year recurrence rate in both primary and previously recurrent tumors emphasizes the importance of tumor excision with margin control and confirms previous studies that MMS offers the highest cure rate for high-risk primary and recurrent SCC. 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. Kwa RE, Campana K, Moy RL. Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;26:1-26. 2. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol 1992;26:467-84. 3. Gallagher RP, Hill GB, Bajdik CD, Coldman AJ, Fincham S, McLean DI, et al. Sunlight exposure, pigmentation factors, and risk of non-melanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 1995;131:164-9. 4. Alam M, Ratner D. Cutaneous squamous cell carcinoma. N Engl J Med 2001;344:975-83.
5. Staples M, Marks R, Giles G. Trends in the incidence of non-melanocytic skin cancer (NMSC) treated in Australia 1985-1995: are primary prevention programs starting to have an effect? Int J Cancer 1998;78:144-8. 6. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer 1998;78:587-93. 7. Weedon D. Tumors of the epidermis. In: Skin pathology. London: Churchill-Livingstone; 1997. pp. 652-4. 8. Roth JJ, Granick MS. Squamous cell and adnexal carcinomas of the skin. Clin Plast Surg 1997;24:687-703. 9. Rudolph R, Zelac DE. Squamous cell carcinoma of the skin. Plast Reconstr Surg 2004;114:82e-94e. 10. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis and survival rates in squamous cell carcinoma of the skin, ear and lip. J Am Acad Dermatol 1992;26:976-90. 11. Shriner DL, McCoy DK, Goldberg DJ, Richard F, Wagner RF Jr. Mohs micrographic surgery. J Am Acad Dermatol 1998;39: 79-97. 12. Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 2002;146(Suppl 61):1-6. 13. Harvey RA, Chaglassian T, Knapper W, Goulian D. Squamous cell carcinoma of the skin in adolescence. Report of a case. JAMA 1977;238:513. 14. Motley R, Kersey P, Lawrence C. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Plast Surg 2003;56:85-91. 15. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27:241-8. 16. Graham G, Clark L. Statistical analysis in cryosurgery of skin cancer. Clin Dermatol 1990;8:101-7. 17. Perez CA. Management of incompletely excised carcinoma of the skin. Int J Radiat Oncol Biol Phys 1991;20:903-4. 18. 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. 19. Rapini RP. Comparison of methods for checking surgical margins. J Am Acad Dermatol 1990;23:288-94. 20. Mohs FE. Chemosurgery: microscopically controlled surgery for skin cancer—past, present and future. J Dermatol Surg Oncol 1978;4:41-54. 21. Mohs FE. Chemosurgery for the microscopically controlled excision of cutaneous cancer. Head Neck Surg 1978;1:150-63. 22. Robins P, Dzubow LM, Rigel DS. Squamous-cell carcinoma treated by Mohs’ surgery: an experience with 414 cases in a period of 15 years. J Dermatol Surg Oncol 1981;7:800-1. 23. Dzubow LM, Rigel DS, Robins P. Risk factors for local recurrence of primary cutaneous squamous cell carcinoma. Treatment by microscopically controlled excision. Arch Dermatol 1982;118:900-2. 24. Jensen P, Hansen S, Moller B, Leivested T, Pfeffer P, Geiran O, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40:177-86. 25. Voyk HD, Lohuis PJ. Mohs micrographic surgery for facial skin cancer. Clin Otolaryngol 2001;26:265-73.
SURGERY
Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years Igal Leibovitch, MD,a Shyamala C. Huilgol, FACD,b,d Dinesh Selva, FRANZCO,a,c Dudley Hill, FACD,d Shawn Richards, FACD,e and Robert Paver, FACDe Adelaide, South Australia, and Sydney, Australia Background: Only a few reports have been published on the long-term outcome of surgical excision of cutaneous squamous cell carcinoma (SCC). Objective: Our purpose was to report the clinical findings and 5-year recurrence rate of all patients with cutaneous SCC treated with Mohs micrographic surgery (MMS) in Australia between 1993 and 2002. Method: This prospective, multicenter case series included all patients with SCC who were monitored by the Skin and Cancer Foundation. The main outcome measures were patient demographics, reason for referral, duration of tumor, site, preoperative tumor size, postoperative defect size, recurrences before MMS, histological subtypes, and 5-year recurrence after MMS. Results: The case series comprised 1263 patients (25.7% female and 74.3% male; P \ .0001) with a mean age of 66 6 13 years. In 61.1% of cases the lesion was a primary tumor, and in 38.9% it was a recurrent tumor. Most of the tumors (96.5%) were on the head and neck area. Recurrent tumors were larger than primary tumors (P \.0001), had a larger postexcision defect (P \.0001), required more levels of excision (P \.0001), and had more cases of subclinical extension (P = .002). Recurrence after MMS was diagnosed in 15 of the 381 patients (3.9%) who completed the 5-year follow-up after MMS. The recurrence rate was 2.6% in patients with primary SCC and 5.9% in patients with previously recurrent SCC (P \ .001). Conclusion: This large prospective series of SCC managed by MMS is characterized by a high percentage of high-risk tumors. The low 5-year recurrence rate with MMS emphasizes the importance of margincontrolled excision. ( J Am Acad Dermatol 2005;53:253-60.)
S
quamous cell carcinoma (SCC) is the second most common skin malignancy after basal cell carcinoma (BCC) in fair-skinned persons.1,2 Reports indicate a significant rise in the incidence of SCC over the past two decades,3,4 and it is estimated that the age-adjusted annual incidence of SCC among white persons in the United States and Canada is 100 to 150 per 100,000 persons.4 In
From the Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences,a the Department of Dermatology,b and the Department of Surgery,c Royal Adelaide Hospital, University of Adelaide; Wakefield Clinic, Adelaided; and Skin and Cancer Foundation Australia, Sydney.e Funding sources: None. Conflicts of interest: None disclosed. Reprint requests: Dr Shyamala Huilgol, Wakefield Clinic, 270 Wakefield St, Adelaide SA 5000. E-mail: [email protected]. sa.gov.au. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.02.059
Australia the estimated annual incidence rate was 321 per 100,000 persons 14 years of age and older in 1995, with a significant latitude gradient, resulting in an incidence of more than 1000 per 100,000 in some northern parts of Australia.5,6 SCC most often arises in areas of direct sun exposure, with a marked predilection for the head and neck.2,4,7-9 These tumors are usually progressively enlarging, but some follow a more aggressive course, are rapidly invasive, and carry a high risk of metastasis.4,7 Treatment modalities for SCC include surgery and other techniques.10 Mohs micrographic surgery (MMS) provides a combination of high cure rate and tissue conservation; hence it is useful for high-risk tumors (recurrent or incompletely excised tumors, mid-facial location, size larger than 2 cm, aggressive histologic changes, and perineural invasion).9-11 The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia (SCFA) with the aim of collecting prospective 253
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Table I. Prior treatments for recurrent squamous cell carcinoma Prior treatments (No. of patients) No. of tx
1 2 3 $4
Cryotherapy (n = 294)
123 91 28 52
(41.8%) (30.9%) (9.5%) (17.7%)
Curettage and cautery (n = 86)
74 (86%) 12 (14.0%) — —
Surgical excision (n = 265)
220 38 6 1
(83%) (14.3%) (2.3%) (0.4%)
RT (n = 17)
16 (94.1%) 1 (5.9%) — —
RT, Radiation therapy; tx, treatments.
data and involved all Mohs surgeons in the country. This first article reports all patients with cutaneous SCC, treated with MMS, who were monitored by the SCFA between 1993 and 2002 and the outcome in patients with a 5-year follow-up. The second part will report the incidence, features, and outcomes of patients with perineural invasion.
METHODS We conducted a prospective, noncomparative, multicenter, interventional case series of patients with cutaneous SCC treated with MMS in Australia and monitored by the SCFA between 1993 and 2002. The selection criteria were all cases with histologically confirmed SCC and treated with MMS. The main data recorded were patient age and gender, reason for referral, duration of tumor, site, recurrences before MMS, preoperative tumor size, histological subtypes and evidence of perineural invasion, number of excision levels, postoperative defect size, and recurrence at 5-years after MMS. 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 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 the number of size groups between the defect and tumor size. All surgeons used a standard fresh-frozen MMS technique with a tissue map and 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 frozensection preparation. Residual tumor was mapped and targeted serial excision performed until the surgical margins were clear. All excision, mapping, and tissue examination was 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. Excision margins for initial and subsequent layers varied according to tumor and site and between different surgeons. Statistical analysis Associations between categorical variables were analyzed by x2 tests, with the Mantel-Haenszel 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 using t tests and analysis of variance; their nonparametric equivalent was used for non-normally distributed data. Analyses were performed using SAS Version 9.1 (SAS Institute Inc., Cary, NC).
RESULTS Patients treated with MMS The study group included 1263 patients who underwent MMS for cutaneous SCC between 1993 and 2002. There were 324 women (25.7%) and 938 men (74.3%) (P \.0001), with a mean age of 66 6 13 years (median, 68 years; range, 21-96 years). In 772 patients (61.1%) the lesion was a primary tumor, and in 491 patients (38.9%) the tumor was recurrent (previously treated with non-Mohs procedures; Table I). The most commonly stated reasons for referral for MMS was tumor site (24.4%) and tumor recurrence (24.1%) (Table II). Patients were mainly referred by a dermatologist (48.3%) or a general practitioner (31.2%). In most patients (657 patients, 52.0%) the tumor age before excision was less than 1 year. As expected, recurrent tumors were present for a longer period than primary tumors (P \.0001; Table III). The majority of tumors were located on the head and neck (96.5%). The most common anatomic sites were the nose (20.0%), cheek and maxilla (19.8%), and auricular region (18.2%). These were also the most common sites in each of the primary and recurrent groups separately (Table IV). Tumor size was less than 2 cm in 838 patients (66.3%); in 273 patients it was less than 1 cm, and in 565 patients it was between 1 and 1.9 cm (Table V).
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Table II. Reason stated for referral for Mohs micrographic surgery Reason for referral
Primary SCC (N = 772)
Tumor site Recurrent tumor Poorly defined tumor Tumor type Incomplete tumor excision Tumor size No details available
238 (30.8%) — 209 (27.1%) 128 (16.6%) 106 (13.7%) 4 (0.5%) 69 (8.9%)
Table III. Tumor age before excision in patients with squamous cell carcinoma treated with Mohs micrographic surgery Tumor age* (y)
Primary SCC (N = 772)
\1 1-5 5-10 [10 NA
527 200 11 5 29
(68.3%) (25.9%) (1.4%) (0.6%) (3.8%)
Previously recurrent SCC (N = 491)
130 274 58 13 16
(26.5%) (55.8%) (11.8%) (2.6%) (3.3%)
Overall (N = 1263)
657 474 69 18 45
(52.0%) (37.5%) (5.5%) (1.4%) (3.6%)
NA, Data not available; SCC, squamous cell carcinoma. *P \ .0001.
Recurrent tumors were significantly larger than primary tumors (P \.0001). The postexcision defect size was less than 2 cm in 428 patients (33.9%), whereas in the majority of patients (66.1%) it was larger than 2 cm (Table VI). Defect sizes in recurrent tumors were larger than primary tumors (P \.0001). Significant subclinical extension, defined as tumor defect exceeding tumor size by at least 2 size groups, was seen in 15.3% of primary tumors and in 23.1% of recurrent tumors (P = .002). The overall percentage of patients with significant subclinical extension was 18.2%. Several anatomic sites (scalp, auricular area, periocular area, nose) were also associated with a significant subclinical extension (P \.0001). The most common histological subtypes were moderately differentiated (444 patients, 35.1%) and well differentiated (440 patients, 34.8%). The poorly differentiated and acantholytic subtypes were less common and were found to be associated with previous recurrence (P = .02; Table VII). Female gender was associated with a moderately differentiated or well-differentiated SCC, whereas male gender was associated with a poorly differentiated or acantholytic SCC (P = .002). The poorly differentiated or acantholytic subtypes were also associated with larger tumor and defect sizes (P \.001), as well as significant subclinical extension (P = .005). Perineural invasion (PNI) was diagnosed in 70 patients, and the data will be presented in part 2 of this study.
Previously recurrent SCC (N = 491)
70 304 56 22 20 3 14
(14.3%) (61.9%) (11.4%) (4.5%) (4.1%) (0.6%) (2.8%)
Overall (N = 1263)
308 304 285 150 126 7 83
(24.4%) (24.1%) (22.6%) (11.9%) (10.0%) (0.5%) (6.6%)
The mean number of levels required for complete tumor excision was 1.60 (median, 1.0; range, 1-7 levels). Recurrent cases required more levels of excision (mean, 1.73; range, 1-6) compared with primary cases (mean, 1.54; range, 1-7) (P \ .0001). The poorly differentiated and acantholytic subtypes also required more levels (mean, 1.86 and 1.82, respectively; P \ .001). It was also found that men required more excision levels than women (1.74 6 0.8 vs 1.4 6 0.7; P \.001). Forty-five patients (3.6%) were treated with adjunctive local radiation therapy after MMS, 37 of whom had PNI. Patients with 5-year follow-up Three hundred eighty-one patients (100 women and 281 men) who completed 5-year follow-up after MMS. The mean age of these patients was 65 6 13 years (median, 66; range, 21-96 years). In 229 patients (60.0%) the lesion was a primary tumor, and in 152 (40.0%) the tumor was recurrent (previously treated with non-Mohs procedures). Most of the tumors were located on the head and neck (96.3%). The most common site was the nose (85 patients, 22.3%), followed by the auricular region (70 patients, 18.4%), cheek and maxilla (69 patients, 18.1%), and the periocular area (39 patients, 10.2%). Tumor size was less than 2 cm in 261 patients (68.5%), less than 1 cm in 86, and between 1 and 1.9 cm in 175. The defect was less than 2 cm in 143 patients (37.5%), whereas in the majority (62.5%) it was larger than 2 cm. The percentage of patients with significant subclinical extension (defined as the defect exceeding tumor size by at least 2 size groups) was 18.6%. The mean number of Mohs stages required for tumor removal was 1.6 6 0.8 (median, 1.0; range, 1-5). The most common histological subtypes were well differentiated and moderately differentiated (44.4% and 36.0%, respectively). The acantholytic and poorly differentiated subtypes comprised 13.5% and 6.4% of cases, respectively. Twenty-five patients with PNI completed a 5-year follow-up period, and these data will be presented in part 2 of this study.
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Table IV. Sites of squamous cell carcinoma treated with Mohs micrographic surgery Site of SCC
Scalp Forehead Periocular area Auricular area Cheek and maxilla Nose Lips Chin and mandible Neck Upper limbs Trunk Genitalia Lower limbs NA
Primary SCC (N = 772)
70 67 73 141 145 147 80 5 16 14 3 1 7 3
(9.1%) (8.7%) (9.5%) (18.3%) (18.8%) (19.0%) (10.4%) (0.6%) (2.1%) (1.8%) (0.4%) (0.1%) (0.9%) (0.4%)
Previously recurrent SCC (N = 491)
43 40 40 89 105 105 28 6 13 9 5
(8.8%) (8.1%) (8.1%) (18.1%) (21.4%) (21.4%) (5.7%) (1.2%) (2.6%) (1.8%) (1.0%) — 5 (1.0%) 3 (0.6%)
Overall (N = 1263)
113 107 113 230 250 252 108 11 29 23 8 1 12 6
(8.9%) (8.5%) (8.9%) (18.2%) (19.8%) (20.0%) (8.6%) (0.9%) (2.3%) (1.8%) (0.6%) (0.1%) (0.9%) (0.5%)
NA, Data not available; SCC, squamous cell carcinoma.
Five-year follow-up data were not available for 882 patients. We compared the parameters of these patients with those who had 5-year follow-up data to identify differences between the two groups. No significant differences between the two groups were identified for age (P = .8), gender (P = .7), tumor age (P = .2), tumor site (P = .2), percentage of previously recurrent cases (P = .4), tumor and defect size (P = .6 and P = .4, respectively), histological subtypes (P = .5), and number of Mohs stages (P = .7). Five-year recurrence data Recurrence at 5-year follow-up after MMS was documented in 15 of 381 patients (3.9%; exact 95% confidence interval [CI], 2.2%-6.4%). There were 6 cases of recurrence at 5 years in the 229 patients with primary SCC (2.6%; exact 95% CI, 1.0%-5.7%), and 9 cases of recurrence in the 152 cases with previously recurrent tumors (5.9%; exact 95% CI, 3.0%-11.9%) (P \ .001) (Table VIII). Two of the cases with recurrence at 5 years were initially treated with adjunctive radiation therapy after MMS. The 15 patients with recurrence at 5 years included 11 men (73.3%) and 4 women (26.7%). The most common site for recurrence was the nose (33.3% of cases) followed by the auricular area (20.0%) and forehead (20.0%). No association was found between tumor site, histological subtypes, tumor size at presentation or postexcision defect, and recurrence at 5 years (P = .4, P = .3, P = .7 and P = .4, respectively). Significant subclinical extension was evident in 4 cases (26.7%) (P = .07). The mean number of levels required in patients with recurrence at 5 years was 2.2 (median, 2.0; range, 1-4 levels), whereas in patients with no recurrence at
5 years it was 1.70 (median, 2.0; range 1-5 levels) (P = .01). No cases of metastatic disease were documented in patients who were initially treated with MMS or in those who completed the 5-year follow-up period.
DISCUSSION The significant increase in the incidence of nonmelanoma skin cancers (NMSCs) over the past two decades has resulted in a growing number of studies on epidemiology, risk factors, and treatment modalities. SCC, which constitutes 20% to 25% of NMSC, is mainly associated with ultraviolet radiation, but other possible risk factors are ionizing radiation, chemical agents (arsenic, polycyclic aromatic hydrocarbons, smoking), genodermatoses (albinism and xeroderma pigmentosum), human papillomavirus infection, immunosuppression, and chronically injured skin (ulcers, burns, sinus tracts, vaccination scars, and chronic skin diseases).4,7-9,12 SCC occurs predominantly in older patients in their seventh decade, but the age range may be much wider; there are rare reports of tumors occurring in the second decade.13 In most series there appears to be a male predominance. In a recent report, Diepgen and Mahler12 reviewed a large number of series from the United States, Europe, and Australia and showed that the male/female ratio in most series of SCC was 2-3:1. A similar male/female ratio (3:1) was found in our study, and the mean age was 66 6 13 years (ranging between 21 and 96 years), correlating with previous reports. SCC is most commonly seen on areas of direct exposure to sun, mainly the head and neck area, upper limbs, and trunk. Analysis of the anatomic distribution in our series showed that more than 96%
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Table V. Preoperative tumor sizes in relation to prior recurrence in patients with squamous cell carcinoma treated with Mohs micrographic surgery
Table VI. Postoperative defect sizes in relation to prior recurrence in patients with squamous cell carcinoma treated with Mohs micrographic surgery
Tumor size* (cm)
Primary SCC (N = 772)
Defect size* (cm)
Primary SCC (N = 772)
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 NA
198 357 119 51 18 8 4 1 16
\1 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-7.9 8-10 [10 NA
32 273 251 98 62 18 12 9 1 16
(25.6%) (46.2%) (15.4%) (6.6%) (2.3%) (1.0%) (0.5%) (0.1%) (2.1%)
Previously recurrent SCC (N = 491)
75 208 118 31 23 10 4 2 20
(15.3%) (42.4%) (24.0%) (6.3%) (4.7%) (2.0%) (0.8%) (0.4%) (4.1%)
Overall (N = 1263)
273 565 237 82 41 18 8 3 36
(21.6%) (44.7%) (18.7%) (6.5%) (3.2%) (1.4%) (0.6%) (0.2%) (2.8%)
NA, Data not available; SCC, squamous cell carcinoma. *P \ .0001.
of tumors were located on the head and neck, most commonly on the nose (20.0%), cheek and maxilla (19.8%), and auricular region (18.2%). Only 3.5% were found on other body areas. Although the predilection for the head and neck may be partly explained by higher sun exposure, there is most likely a strong referral bias in our series for treatment of lesions in these areas with Mohs surgery.14 Histologically, SCC is composed of nests of squamous epithelial cells that arise from epidermis and invade the dermis. The degree of anaplasia in the tumor nests is used to grade SCC, based on a subjective assessment of differentiation.7 The categories are ‘‘well’’ differentiated (the relative proportion of anaplastic cells is low, and the architecture resembles normal epidermis), ‘‘moderately’’ differentiated (half of the cells or more are anaplastic), and ‘‘poorly’’ differentiated (all cells are anaplastic, and diagnosis is based on keratin markers). The acantholytic variant, which is more common on the head and neck, accounts for only 2% to 4% of all SCC cases.7 It consists of nests of squamous cells with central acantholysis leading to an impression of gland formation and is considered more aggressive.7 The most common histological subtypes in our study were the moderately differentiated (35.1%) and well differentiated (34.8%) (Table VII). The more aggressive subtypes (poorly differentiated and acantholytic) constituted 20% of cases, which is higher than their general proportion in SCC cases.7 This relatively high proportion of aggressive subtypes is undoubtedly influenced by referral bias for MMS. As demonstrated in Table II, almost 35% of cases were referred to Mohs surgery because of tumor histology or a poorly defined lesion, which is more common with these subtypes, and may explain their relative pre-
(4.1%) (35.4%) (31.2%) (12.7%) (8.0%) (2.3%) (1.6%) (1.2%) (0.1%) (2.1%)
Previously recurrent SCC (N = 491)
6 117 157 100 41 29 20 7 2 12
(1.2%) (23.8%) (32.0%) (20.4%) (8.3%) (5.9%) (4.1%) (1.4%) (0.4%) (2.4%)
Overall (N = 1263)
38 390 408 198 103 47 32 16 3 28
(3.0%) (30.9%) (32.3%) (15.7%) (8.2%) (3.7%) (2.5%) (1.3%) (0.2%) (2.2%)
NA, Data not available; SCC, squamous cell carcinoma. *P \ .0001.
ponderance. Not surprisingly, less-differentiated histology was associated with previous recurrence (P = .02), larger tumor and defect sizes (P \ .001), significant subclinical extension (P = .005), as well as more levels of excision (P\.001). Similar findings, which emphasize the importance of tumor excision with margin control, were reported by Brodland and Zitelli,15 who studied a group of 141 primary tumors. They concluded that a 6-mm margin was required to clear 95% of high-risk tumors ([2 cm, periocular location, and poor histologic differentiation), compared with only 4 mm for low-risk SCC. Four hundred ninety-one patients (38.9%) in our series had recurrent tumors, all of whom had been treated previously with modalities other than MMS (Table I). These recurrent tumors were larger than primary tumors (P \.0001), required more levels of excision (P \ 0.0001), and had larger postexcision defect sizes (P \ .0001). Significant subclinical extension, defined as tumor defect exceeding tumor size by at least 2 size groups, was seen in 15.3% of primary tumors and 23.1% of recurrent tumors (P = .002). The significant subclinical extension in our series further emphasizes the importance of margin-controlled excision for SCC and may explain the failure rate in those treatment modalities based solely on clinical margins (eg, radiation therapy) with no histological control. Furthermore, recurrent lesions treated with destructive modalities such as cryotherapy may have architectural changes that obscure monitoring, delay clinical detection of recurrence, and make later margin-controlled excision more difficult. In addition, the fibrosis may entrap malignant cells, favor deep extension by preventing upward migration, and, again, delay clinical detection.
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Table VII. Histologic subtypes of squamous cell carcinoma treated with Mohs micrographic surgery Histologic subtype
Primary SCC (N = 772)
Well differentiated Moderately differentiated Poorly differentiated* Acantholytic* NA
269 281 46 80 96
(34.8%) (36.4%) (6.0%) (10.4%) (12.4%)
Previously recurrent SCC (N = 491)
171 163 51 76 30
(34.8%) (33.2%) (10.4%) (15.5%) (6.1%)
Overall (N = 1263)
440 444 97 156 128
(34.8%) (35.1%) (7.7%) (12.3%) (10.1%)
NA, Data not available; SCC, squamous cell carcinoma. *P = .02.
Table VIII. Five-year recurrence rate after Mohs micrographic surgery in relation to previous recurrence of squamous cell carcinoma 5-year recurrence
Yes No %*
Primary SCC (N = 229)
Previously recurrent SCC (N = 152)
Overall patients with 5 years follow-up (N = 381)
6 223 2.6
9 143 5.9
15 366 3.9
*P \ .001.
The choice of treatment options for cutaneous SCC is based on variables such as patient factors (age, sex, general health), tumor characteristics (size, location, histologic subtype), as well as the treating physician’s and patient’s preference and available resources.8 Nonsurgical treatments used for SCC include cryotherapy and radiation therapy. Cryotherapy, using liquid nitrogen, is generally used to treat only small and well-defined low risk tumors, where it was reported to achieve short-term recurrence rates as low as 3%.10,14,16 This treatment modality is generally contraindicated in high-risk tumors, such as recurrent, large, and mid-facial SCC, with aggressive histology.14 Radiation therapy is a preferred treatment modality in older and disabled patients with large tumors, when surgical treatment may not be appropriate.4,14 This treatment is relatively contraindicated in cases with ill-defined clinical tumor margins.14 Rowe, Carroll, and Day10 reviewed all studies since 1940 on the prognosis and treatment of cutaneous SCC. They found that in 633 cases of primary SCC, with less than 5 years follow-up, the recurrence rate with radiation therapy was 6.7%, whereas in 160 patients, with at least 5 years of follow-up, the recurrence rate was 10%. The recurrence rate with radiotherapy for more advanced stages of primary tumors and for previously recurrent tumors reached 35% to 50%.17 In a recent report by Kwan, Wilson, and Moravan18 the 4-year recurrence rate for locally advanced SCC was as high as
42%, occurring very early after treatment (median 5 months). Radiation therapy is also used as adjunctive postsurgical treatment of high-risk tumors with perineural invasion and positive surgical margins and in the control of metastatic disease.9 Forty-five patients in our series (3.6%) were treated with postsurgical radiation therapy, mainly in cases with PNI. This aspect in the treatment of SCC with PNI is further discussed in part 2 of our report. Curettage and cautery is also reported to have excellent cure rates in SCC, but once again, this is based on series reporting the outcome for low-risk tumors.14 Rowe, Carroll, and Day10 calculated a 5-year recurrence rate of 3.7% in primary tumors, previously reported in other series. Surgical excision is the most frequent treatment modality for SCC and is considered the treatment of choice for most tumors. Excision without margin control is estimated to have a 5-year recurrence rate of 5% to 18.7% for primary tumors in different locations10,14,15 and more than 23% for previously recurrent SCC.10 In a review of 1006 patients with primary SCC treated with surgical excision and followed up for less than 5 years, Rowe, Carroll, and Day10 calculated a 5-year recurrence rate of 5.7%, whereas in 124 patients with 5 years or more of follow-up, the recurrence was 8.1%. They also found a 5-year recurrence rate of 23.3% in 34 patients with previously recurrent tumors treated with surgical excision. 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.19 For that reason, it is generally accepted that MMS is indicated in high-risk tumors.8,11,14 A few large-scale studies have previously evaluated the role of MMS in treating cutaneous SCC (Table IX). Our study, which is based on the Australian MMS database, is one of the largest reported prospective nationwide series of patients
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Table IX. Comparative clinical and 5-year recurrence data on Mohs micrographic surgery for squamous cell carcinoma Mohs20,21
Study years Tumor location Overall number of tumors with 5-y follow-up (18/28) Overall 5-y recurrence (%) (18/28)
Robins et al22,23
Holmkvist & Roenigk*
Our study
NA Head 2551 (NA)
1965-1980 Head 414 (18)
1986-1989 Lips 50 (NA)
1993-2002 Mainly head and neck 381 (229/152)
5.6 (NA)
6.7 (1.8/3.4)
8.0 (NA)
3.9 (2.6/5.9)
18, Primary; 28, recurrent; NA, not available. *Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years. J Am Acad Dermatol 1998;38:960-6.
with SCC managed by MMS. This series is characterized by a high percentage of high-risk head and neck tumors. The 5-year recurrence rate in primary cases was 2.6%, whereas in previously recurrent cases it was 5.9%. The overall 5-year recurrence rate for all 381 patients who completed the follow-up period was 3.9%. These recurrence rates are low, particularly in view of the significant number of high-risk tumors included. The largest series of patients with SCC, treated with MMS and followed up for a period of 5 years, was reported by Mohs.20,21 He found an overall 5-year recurrence rate of 5.6% in a series of 2551 patients with SCC. Robins, Dzubow, and Rigel22 and Dzubow, Rigel, and Robins23 reported similar 5-year recurrence rates (6.7%) in a series of 414 patients with primary SCC treated with MMS. In their retrospective literature review of treatment modalities for SCC since 1940, Rowe, Carroll, and Day10 found that the 5-year recurrence rate for 2065 cases of primary SCC treated with MMS was 3.1%, whereas for 151 previously recurrent cases it was 10.0%. MMS was also shown to provide the highest cure rates for larger tumors ([2 cm), as well as those with poorly differentiated histologic features, compared with other treatments. They concluded that all non-Mohs treatment modalities achieve similar cure rates, but MMS offered the best cure rates with the lowest recurrence rates and should be considered the treatment of choice for high-risk SCC. Several factors have been found to correlate with a higher risk of recurrence and metastasis of SCC. Tumors larger than 2 cm in diameter are twice as likely to recur locally (15.2% vs 7.4%) and 3 times as likely to metastasize (30.3% vs 9.1%) as tumors smaller than 2 cm.10,14 Tumor depth greater than 4 mm (Clark level IV) is associated with an increased risk of metastasis compared with more superficial lesions (45.7% and 6.7%, respectively).10,14 Tumor location in previous areas treated by radiation, thermal injury, Bowen’s disease, chronic ulcers, as well as specific sites such as the ear, lips, and genital area, were also found to be associated with a higher risk of
recurrence and metastasis.9,10,14 Tumors with poor histologic differentiation (as well as acantholytic features and PNI) are associated with a higher recurrence and metastatic rate compared with welldifferentiated tumors (28.6% vs 13.6% and 32.8% vs 9.2%, respectively).7,10,14 Locally recurrent SCCs have a higher risk (25%-45%) of further recurrence and metastasis after secondary treatment.9,10 Another important factor is the immune status of the patient; immunocompromised patients are at increased risk for recurrence and metastatic lesions.10 Recent studies show that SCC is up to 65 times as likely to develop in transplant recipients as in age-matched controls.24 In our study we documented tumor factors such as size, location, histology, and previous recurrence, but data on tumor depth, previous skin disease, and the immune status of the patient were not available. The main predictors for recurrence in our study were previous recurrence, significant subclinical extension, and more Mohs levels (P \ .001, P = .07, and P = .01, respectively). We found no association between tumor site, histological subtype, tumor size at presentation, or postexcision defect and recurrence at 5 years. Although MMS provides the highest cure rate for high-risk SCC, there were still recurrences in our series, especially in previously recurrent tumors. The causative factors include technical difficulties and errors during Mohs surgery; the selection of a more aggressive group of tumors; and the presence of discontinuous tumor and ‘‘skip’’ lesions, resulting from previous treatment, which make margincontrolled excision more difficult. For this reason, Mohs surgeons will usually remove the entire scar from previous treatment as well as the recurrent tumor and then evaluate the margins of the surrounding tissue.9,25 Although Mohs surgery serves as a method for complete tumor removal with normal tissue conservation, there are Mohs surgeons who apply the narrowest margins possible even for higher risk tumors, and this may result in lower cure rates. The data on excisional margins that were
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used by Mohs surgeons in our series were not recorded; therefore the role of this variable in tumor recurrence could not be analyzed. Only 30.2% of the patients in our series (381/1263), who were initially treated with MMS, completed the 5-year follow-up period. Although these missing data are certainly important, we found no significant differences between the patients who completed the follow-up and those who did not, and we believe that the information obtained after 5 years gives a valuable estimation of the cure rate for highrisk SCC. In conclusion, this study is the largest reported prospective nationwide series of SCC managed by MMS. This series is characterized by a high percentage of poorly differentiated large head and neck tumors, as well as recurrent cases. These factors contribute to a more aggressive nature and define them as high risk tumors. The relatively low 5-year recurrence rate in both primary and previously recurrent tumors emphasizes the importance of tumor excision with margin control and confirms previous studies that MMS offers the highest cure rate for high-risk primary and recurrent SCC. 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.
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