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Basosquamous Carcinoma Treatment with Mohs Micrographic Surgery
Igal Leibovitch, M.D.1 Shyamala C. Huilgol, M.B.B.S.2 Dinesh Selva, M.B.B.S.1,3 Shawn Richards, M.B.B.S.4 Robert Paver, M.B.B.S.4 1
Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia.
2
Department of Dermatology, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia.
3
Department of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
4
Skin and Cancer Foundation Australia, Sydney, New South Wales, Australia.
BACKGROUND. Basosquamous carcinoma (BSC) is a rare tumor defined as a basal cell carcinoma (BCC) differentiating into squamous cell carcinoma (SCC). It is reported to have a high rate of recurrence with standard wide local excision. The aim of the current study was to report a large series of patients with BSC treated with Mohs micrographic surgery (MMS). METHODS. The prospective, multicenter case series included all patients in Australia treated with MMS for BSC, who were monitored by the Skin and Cancer Foundation Australia between 1993 and 2002.
RESULTS. Most of the 178 tumors (95.6%) were located in the head and neck area. Recurrent tumors occurred in 47.8% of patients. The tumors were diagnosed initially as BCC in 87.4% and as SCC in 12.0% of patients. Perineural invasion was recorded in 7.9% of patients with data available. Most of these (69.0%) were previously recurrent tumors. Of 98 patients who completed a 5-year follow-up period after MMS, 4 (4.1%) had disease recurrence. CONCLUSIONS. The low 5-year disease recurrence rate of BSC with MMS emphasized the importance of margin-controlled excision using MMS. Cancer 2005;104: 170 –5. © 2005 American Cancer Society. KEYWORDS: basosquamous carcinoma, Mohs micrographic surgery, disease recurrence, perineural invasion.
B
The authors thank the Skin and Cancer Foundation Australia and the participating Mohs surgeons for their generosity in providing the data for the current article. The Mohs surgeons involved were Dr. Phillip Artemi, Dr. John Coates, Dr. Brian De’Ambrosis, Dr. Timothy Elliott, Dr. Gregory Goodman, Dr. Irene Grigoris, Dr. Dudley Hill, Dr. Shyamala Huilgol, Dr. Michelle Hunt, Dr. David Leslie, Dr. Robert Paver, Dr. Shawn Richards, Dr. William Ryman, Dr. Robert Salmon, Dr. Margaret Stewart, Dr. Howard Studniberg, Dr. Carl Vinciullo, and Dr. Perry Wilson. The authors also thank Emmae Ramsay (statistician), Department of Public Health University of Adelaide, for her help and advice in the statistical analysis of data. Address for reprints: Shyamala Huilgol, M.B.B.S., Wakefield Clinic, 270 Wakefield Street, Adelaide, South Australia, Australia 5000; Fax: (011) 61-88224-0414; E-mail:
[email protected] Received November 1, 2004; revision received March 3, 2005; accepted March 14, 2005.
asosquamous carcinoma (BSC) was first reported as a distinct histologic variant in 1910 by MacCormac in a series of rodent ulcers.1 It was described as coexistence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with no transition zone between them. Since then there has been considerable debate regarding whether this tumor really exists or whether it is only a collision of two cutaneous tumors or a keratinizing BCC.1–9 Recent reports using immunohistochemical and staining techniques of BSC tumor specimens show areas of definitive BCC and SCC with a transition zone between them, suggesting differentiation of one of the tumors into the other.10,11 It is now believed that BCC cells, being pluripotential cells, differentiate into the more aggressive squamous cells.9 BSC is a rare tumor with an estimated incidence rate of ⬍ 2% of all skin carcinomas.6,7,10 Nevertheless, this tumor may be locally aggressive with the potential to metastasize.6,9,12,13 The rarity of this tumor, the pattern of growth, and the initial lack of diagnostic criteria have resulted in only a few studies evaluating the best treatment options for patients. The Australian Mohs surgery database was initiated in 1993 by the Skin and Cancer Foundation Australia with the aim of evaluating outcomes after Mohs micrographic surgery (MMS), and all Mohs surgeons in the country participated. Our prospective study presents
© 2005 American Cancer Society DOI 10.1002/cncr.21143 Published online 31 May 2005 in Wiley InterScience (www.interscience.wiley.com).
BCC and MMS/Leibovitch et al.
all patients treated with MMS for BSC who were monitored by the Skin and Cancer Foundation Australia.
MATERIALS AND METHODS This is a prospective, noncomparative, multicenter, interventional case series of patients with BSC treated with MMS in Australia and monitored by the Skin and Cancer Foundation Australoia, between 1993 and 2002. All patients were treated by a certified Mohs surgeon, using standard fresh-frozen MMS techniques. Data were collected by the Skin and Cancer Foundation Australia. The criteria for selection were all cases with BSC diagnosed histologically and treated with MMS. The following parameters were recorded: patient identification number, age, gender, reason for referral, evidence of perineural invasion (PNI), duration of tumor, site, disease recurrences beforeo MMS, preoperative tumor size, and postoperative defect size. Post-MMS disease recurrence was defined as local disease recurrence due to persistent disease. Tumor and postoperative defect size were defined into 8 groups based on the maximum dimension using a straight rule: 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, and 8 –10 cm. All surgeons used a standard fresh-frozen MMS technique with a tissue map and color coding of the excised tissue specimen. Frozen sections of the entire outer margin in a continuous layer were prepared, and the tissue specimen was stained with hematoxylin and eosin. A trained Mohs technician performed all frozen section preparations. The residual tumor was mapped and targeted serial excision was performed until the surgical margins were clear. All excision, mapping, and tissue specimen evaluation were performed 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 among surgeons. All initial tumor biopsies before MMS were evaluated by a dermopathologist. The final histologic diagnosis was done on a debulking specimen before MMS, and/or on the frozen sections seen on the routine MMS sections, according to the surgeon’s preferences. In several centers, the final histologic specimens were also reviewed by an experienced dermopathologist. PNI was confirmed on the debulking specimens or on the final Mohs sections. Histologic definition of BSC was based on identifying areas of both BCC (with basaloid cells which are larger, paler, and rounder than solid BCC) and SCC (with squamoid cells with abundant eosinophilic cy-
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TABLE 1 Sites of BSC Treated with Mohs Micrographic Surgery Site of BSC
No. of patients (n ⴝ 178) (%)
Scalp Forehead Temple Periocular Maxilla Cheek Auricular area Mastoid Nose Lips Chin and mandible Neck Upper limbs Trunk Lower limbs
5 (2.8) 12 (6.7) 16 (9.0) 20 (11.2) 1 (0.6) 17 (9.6) 33 (18.5) 1 (0.6) 59 (33.1) 2 (1.1) 2 (1.1) 2 (1.1) 2 (1.1) 4 (2.2) 2 (1.1)
BSC: basosquamous carcinoma.
toplasm) with a transition zone (intermediate cells) between them.14
Statistical Analysis Associations between categorical variables were analyzed using chi-square tests, with the Mantel–Henszel test for linear association where appropriate. The Wilcoxon two-sample test was used for nonnormally distributed data. Exact 95% confidence intervals (95% CI) were calculated for the disease recurrence rates. Analyses were performed using SAS, version 9.1 (SAS Institute Inc., Cary, NC).
RESULTS One hundred seventy-eight patients with 178 tumors were included in the study. There were 115 males and 63 females (P ⬍ 0.001, for null hypothesis of equal distribution between males and females) with a mean age of 63 ⫾ 11 years (median, 58 years; range, 25–90 years). Most tumors (170 of 178 [95.6%]) were located in the head and neck area, mainly on the nose (59 patients [33.1%]), auricular area (33 patients [18.5%]), and periocular area (20 patients [11.2%]). Only 8 tumors (4.4%) were located outside the head and neck area (Table 1). The most common reason for referral for MMS was tumor recurrence (64 patients [36.0%]) and tumor site (56 patients [31.5%]) (Table 2). Tumor age before MMS was ⬍ 1 year in 60 patients (33.7%), 1–5 years in 87 patients (48.9%), 6 –10 years in 14 patients (7.9%), and ⬎ 10 years in 7 patients (3.9%). Data concerning tumor age were not available for 10 patients (5.6%). The lesion was a recurrent tumor (previously treated with a standard lo-
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TABLE 2 Reason Stated for Referral for Mohs Micrographic Surgery
TABLE 4 Tumor Sizes in Relation to Previous Disease Recurrence in Patients with BSC
Reason for referral
No. of patients (n ⴝ 178) (%)
Recurrent tumor Tumor site Poorly defined Tumor type Incomplete tumor excision No details available
64 (36.0) 56 (31.5) 33 (18.5) 12 (6.7) 8 (4.5) 5 (2.8)
TABLE 3 Previous Treatments for BSC
Tumor size (cm)a
Primary BSC (n ⴝ 93) (%)
Previously recurrent BSC (n ⴝ 85) (%)
Overall (n ⴝ 178) (%)
⬍1 1–1.9 2–2.9 3–3.9 4–4.9 5–5.9 6–7.9 8–10
31 (33.3) 46 (49.5) 11 (11.8) 3 (3.2) 2 (2.2) — — —
12 (14.1) 38 (44.7) 24 (28.2) 7 (8.2) 2 (2.3) 1 (1.2) 1 (1.2) —
43 (24.2) 84 (47.2) 35 (19.7) 10 (5.6) 4 (2.2) 1 (0.6) 1 (0.6) —
Previous treatments No. of repeated treatments 1 2 3 ⱖ4
Cryotherapy (n ⴝ 39) (%)
Curettage and cautery (n ⴝ 15) (%)
Surgical excision (n ⴝ 31) (%)
RT (n ⴝ 6) (%)
19 (48.7) 8 (20.5) 2 (5.1) 10 (25.6)
12 (80.0) 2 (13.3) — 1 (6.7)
17 (54.8) 9 (29.0) 1 (3.2) 4 (12.9)
6 (100) — — —
BSC: basosquamous carcinoma; RT: radiotherapy.
cal excision) in 85 patients (47.8%) and the lesion was a primary nonrecurrent tumor in 93 patients (52.2%). Initial treatments before MMS are summarized in Table 3. Initial biopsy before MMS was performed for 175 patients. Of these 175 patients, BSC was diagnosed correctly in 24 patients (13.7%), the initial diagnosis was reported as BCC in 129 patients (73.7%), as SCC in 21 patients (12.0%), and as SCC in situ in 1 patient (0.6%). Clinical tumor size before MMS was ⬍ 2 cm in 127 patients (71.4%), ⬍ 1 cm in 43 patients, and 1–1.9 cm in 84 patients (Table 4). Previous recurrent tumors were larger than primary tumors (P ⬍ 0.001). The postexcision defect size was ⬍ 2 cm in 74 patients only (41.6%), whereas it was ⬎ 2 cm in the majority of patients (58.4%) (Table 5). Defect sizes in previous recurrent tumors were larger than primary tumors (P ⬍ 0.001). The average number of excision levels required for complete removal of the tumor during MMS was 1.7 ⫾ 0.7 (median, 2.0; range, 1– 6). There was no difference in the median number of levels in the primary and recurrent tumor groups (2.0 levels in both). For 101 tissue specimens (56.7%), the final histologic diagnosis was made by the Mohs surgeon, and for 77 specimens (43.3%), the final diagnosis was based on a review by an experienced dermopathologist as well. PNI data were available for 165 patients (92.7%). For 13 of them (7.9%), PNI was evident. Nine
BSC: basosquamous carcinoma. a P ⬍ 0.001.
TABLE 5 Defect Sizes in Relation to Previous Disease Recurrence in Patients with BSC Defect size (cm)a
Primary BSC (n ⴝ 93) (%)
Previously recurrent BSC (n ⴝ 85) (%)
Overall (n ⴝ 178) (%)
⬍1 1–1.9 2–2.9 3–3.9 4–4.9 5–5.9 6–7.9 8–10
2 (2.1) 51 (54.8) 20 (21.5) 11 (11.8) 3 (3.3) 3 (3.3) 2 (2.1) 1 (1.1)
1 (1.2) 20 (23.5) 33 (38.8) 11 (12.9) 9 (10.6) 3 (3.5) 7 (8.2) 1 (1.2)
3 (1.7) 71 (39.9) 53 (29.8) 22 (12.4) 12 (6.7) 6 (3.4) 9 (5.1) 2 (1.1)
BSC: basosquamous carcinoma. a P ⬍ 0.001.
of the 13 patients with PNI (69.0%) had previous recurrent tumors (P ⫽ 0.09). Three patients with PNI were treated with adjunctive radiotherapy. Five-year follow-up data were available for 98 patients (55.1%). Another 7 patients (3.9%) died of unrelated reasons, and the other 73 patients (41%) did not complete the follow-up period, and could not be contacted after the 5-year period. Local tumor recurrence was evident in 4 of the 98 patients (4.1%) (exact 95% CI, 2.34 – 8.3%) (Table 6). In 2 patients (2.0%), who were diagnosed with a nose BSC, there was tumor spread to regional lymph nodes. One of them (1.0%) died of intracranial tumor extension. Disease recurrence was observed in 1 of the 6 patients with PNI who completed the 5-year follow-up (16.7%). No disease recurrence was evident in 2 of the 3 patients with PNI who were treated with adjunctive radiotherapy and completed the 5-year follow-up. We compared the group of 98 patients who com-
BCC and MMS/Leibovitch et al.
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TABLE 6 Summary of Patients with Disease Recurrence after Mohs Micrographic Surgery
Patient age
Gender
Tumor site
Previous disease recurrence
Tumor size (cm)
Mohs levels
Defect size (cm)
PNI
Disease recurrence Local disease recurrence at 4 yrs Local disease recurrence at 3 yrs and regional lymph node spread Local disease recurrence and ⫹ cervical lymph node metastasis at 2 yrs Local disease recurrence at 3 yrs
66
M
Neck
No
1–1.9
3
8–10
No
41
F
Nose
Yes
⬍1
1
1–1.9
No
64
F
Nose
No
1–1.9
2
1–1.9
No
71
M
Temple
Yes
6–7.9
1
8–10
Yes
Post disease recurrence treatment
Comments
Excision and ⫹ RT Excision and ⫹ RT
Died from intracranial extension
Neck dissection and ⫹ RT
Alive
RT
PNI, perineural invasion; M: male; RT, radiotherapy; LN, lymph nodes; F: female.
pleted the 5-year follow-up period with the other 80 patients with BSC who did not complete the 5-year follow-up. We found no statistically significant differences for the major clinicodemographic parameters (age, gender, previous disease recurrence, tumor and defect size, subclinical extension, and number of Mohs levels) between the two groups.
DISCUSSION BSC is a rare skin carcinoma that occurs predominantly in fair-skinned individuals. Although patients usually present in the fifth to eighth decades of life,6,7,12 the age range may be much wider, and there are reports of tumors occurring in the second decade.7,12 There appears to be a significant male predominance in most series. In the current study, 64% of patients affected by BSC were males (P ⬍ 0.001), and the mean age was similar to previous reports (63 ⫾ 11 years). The age at presentation ranged from 25 to 90 years. BSC is most commonly seen on the head and neck, mainly involving the central face. In the series reported by Borel,6 97% of the tumors were located on the head and neck. Other authors found a head and neck location in 82%12 and 96%13 of patients. The anatomic distribution in our series was similar, with ⬎ 95% of tumors located on the head and neck, most commonly on the nose (33.1%), auricular area (18.5%), and periocular area (11.2%). Only 8 tumors (4.4%) were found on the trunk and limbs. 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 of facial tumors with MMS. The clinical and histologic diagnosis of BSC may be problematic. Clinically, it is usually a slow-growing tumor that cannot be differentiated from other types of BCC or SCC. Histologically, there are areas of BCC with typical basaloid cells that are larger, paler, and rounder than solid BCC, and areas of SCC with squamoid cells that have abundant eosinophilic cytoplasm. A transition zone with intermediate cells is evident between the area of BCC and SCC tumor cells.12,14 Peripheral palisading is rare and there is minimal stromal retraction.8 The cell of origin is unknown, but the pluripotential basal cell is a possible candidate.12 An incorrect histopathologic diagnosis is not uncommon, especially if only a superficial biopsy is obtained. In our series, initial biopsy before MMS was performed for 175 patients. The initial diagnosis was reported as BCC for 73.7% of patients, and as SCC for 12% of patients. A correct diagnosis of BSC was made for only 13.7% of these patients. Although all initial biopsy specimens were evaluated by dermopathologists who are very experienced in skin tumor pathologies, the low rate of correct diagnosis of BSC is probably due to the small biopsy specimens. The final diagnosis is best established on the larger specimens taken during tumor removal. In the current series, the diagnosis was either made only by the Mohs surgeons (56.7% of specimens), based on the
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criteria described earlier, or in conjunction with a dermopathologist (43.3% of specimens). All Mohs surgeons in Australia, who participated in our study, were all very experienced in skin tumor diagnosis and treatment, given the very high incidence of these tumors in the country. Although not all tissue specimens were reviewed by a dermopathologist, we believe that the histologic diagnosis given by the surgeons is very reliable. The treatment options for patients with BSC are excision, radiotherapy, and MMS.15 Most authors agree that surgical excision is probably the treatment of choice. Surgical margins should be wider than those for low-risk BCC due to the infiltrative growth pattern of this tumor. Nevertheless, high disease recurrence rates have been reported despite wide local excision. Borel6 reported a local disease recurrence rate of 45.7% after wide excision for BSC in 35 patients with a follow-up period of ⬍ 1 year. Martin et al.12 found 9 (32.1%) posttreatment disease recurrences in a series of 28 patients with a median follow-up period of 5 years. Schuller et al.7 reported a lower local disease recurrence rate of 12.1% in 33 patients with BSC treated with surgical excision. Standard histologic assessment of excised tissue specimens with breadloaf sectioning assesses only 0.2% of the margins. In contrast, MMS utilizes en-face sections of the entire outer surface of the excised tissue specimen, thereby assessing close to 100% of the peripheral and deep margins.16 The ability to detect and excise subclinical marginal tumor extension with MMS is helpful in dealing with an aggressive tumor that also has a significant metastatic potential. Although there is a significant body of literature reporting the use of MMS in the treatment of BCC and SCC, few studies have evaluated MMS in the treatment of BSC. In a recent retrospective series, Bowman et al.13 reported 28 patients with BSC who underwent MMS. Their study evaluated the extent of local invasion and distant metastases. however, no recurrence and follow-up data were available. Our study, to the best of our knowledge, is the largest prospective series reporting the effectiveness of MMS in treating patients with BSC. We found a 5-year local recurrence rate of 4.1%, which is significantly lower than that reported after standard surgical excision. Only 55.1% of the patients in our series, who were initially treated with MMS, completed the 5-year follow-up period. This lack of follow-up is certainly a possible bias as some of the patients with disease recurrence were not identified. 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. Therefore, we
believe that the information obtained after 5 years gives a valuable estimation of the cure rate for highrisk SCC. PNI is an uncommon phenomenon in skin carcinoma.17 It describes tumor growth in and around nerves, and is estimated to be present in ⬍ 5% of skin carcinomas.18,19 Tumors exhibiting PNI have a higher rate of morbidity and mortality, especially in the head and neck region.17,19,20 PNI may be a feature of BSC. Martin et al.12 demonstrated that patients with BSC and PNI have higher rates of metastasis and local disease recurrence in comparison to patients without PNI. In their series, 55% of patients with recurrent BSC had PNI compared with only 5.3% of patients with primary BSC. In our series, PNI was recorded in 7.9% of patients with data available (165 patients). This incidence is lower than that previously reported for BCC (1%),17 and is similar to the incidence in SCC (2.5–14%),17 demonstrating the more aggressive nature of BSC. Most cases of PNI (69.0%) occurred in previously treated tumors. Although this was not statistically significant, because of the few cases, we believe that it still emphasizes the importance of initial definitive tumor treatment. Five-year follow up data after MMS were available for six patients with PNI. Disease recurrence was reported in 1 of these patients (16.7%), compared with 3 of 92 cases (3.2%) of BSC with no PNI. This, again, demonstrates the more aggressive nature of tumors with PNI and the importance of complete excision with margin control. Three patients in the current series were treated with adjunctive radiotherapy for PNI, and there was no disease recurrence in 2 of them who completed the 5-year follow-up. Although radiotherapy may play an important role in postsurgical treatment of cutaneous carcinomas with PNI, there is no conclusive evidence in the literature to support this treatment after MMS.17 There were 85 patients in our series with recurrent tumors, all of whom had been treated previously with modalities other than MMS (Table 3). These recurrent tumors were significantly larger than the primary tumors (Table 4), had a higher rate of PNI, and had larger postoperative defects (Table 5). These findings further emphasize the importance of early detection of BSC and treatment with margin control to reduce the risk of disease recurrence. To our knowledge, the Australian MMS database contains the largest reported prospective series of BSC cases managed with MMS. The 5-year disese recurrence rate in the current series was 4.1%, which is significantly lower than the rates reported for wide excision. As recurrent cases of BSC are associated with both increased local aggressiveness and metastasis,
BCC and MMS/Leibovitch et al.
we suggest complete excision of this tumor with MMS as the treatment of choice.
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11. Jones MS, Helm KF, Maloney ME. The immunohistochemical characteristics of the basosquamous cell carcinoma. Dermatol Surg. 1997;23:181–184. 12. Martin RC 2nd, Edwards MJ, Cawte TG, Sewell CL, McMasters KM. Basosquamous carcinoma: analysis of prognostic factors influencing recurrence. Cancer. 2000;88: 1365–1369. 13. Bowman PH, Ratz JL, Knoepp TG, Barnes CJ, Finley EM. Basosquamous carcinoma. Dermatol Surg. 2003;29:830 – 832. 14. Weedon D. Tumors of the epidermis. In: Weedon D, editor. Skin pathology. New York: Churchill Livingstone, 1997:650. 15. Kuijpers D, Thissen MR, Neumann MH. Basal cell carcinoma: treatment options and prognosis, a scientific approach to a common malignancy. Am J Clin Dermatol. 2002; 3:247–259. 16. Rapini RP. Comparison of methods for checking surgical margins. J Am Acad Dermatol. 1990;23:288 –294. 17. Feasel AM, Brown TJ, Bogle MA, Tschen JA, Nelson BR. Perineural invasion of cutaneous malignancies. Dermatol Surg. 2001;27:531–542. 18. Mendenhall WM, Amdur RJ, Williams LS, Mancuso AA, Stringer SP, Mendenhall NP. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck. 2002; 24:78 – 83. 19. McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys. 2000;47:89 –93. 20. Matorin PA, Wagner RF Jr. Mohs micrographic surgery: technical difficulties posed by perineural invasion. Int J Dermatol. 2002;31:83– 86.
