Cutaneous squamous cell carcinomas of the lower extremity: A distinct subset of squamous cell carcinomas Changhyun Kim, BS,a Christine J. Ko, MD,a,b and David J. Leffell, MDa New Haven, Connecticut Background: Some patients develop a disproportionate number of cutaneous squamous cell carcinomas (SCCs) on their lower extremity (LE). Objective: We sought to characterize the clinical features, treatment, and outcome in patients who develop multiple LE SCCs. Methods: We identified 22 patients with 4 or more biopsy-diagnosed LE SCCs during a 4.5-year study period. The location, size, treatment, and clinical outcome of each LE SCC were recorded. Results: Of the 22 patients studied, 18 were female. Of the 360 SCCs our patients developed, 260 (72.2%) were on the LE. The incidence of SCCs in these patients was nearly 7 times greater than the incidence of basal cell carcinoma in the same patients. Limitations: The number of patients is small and limits definitive conclusions about prevalence of SCCs on the LE in the general population. Conclusions: LE SCCs are a distinct subset of cutaneous SCCs and may have distinctive clinical features and biologic behavior requiring additional study. ( J Am Acad Dermatol 2014;70:70-4.) Key words: basal cell carcinoma; carcinogen; epidemiology; female; immunosuppression; leg; lower extremity; squamous cell carcinoma; ultraviolet radiation.
E
nvironmental ultraviolet (UV) radiation has been widely acknowledged as the single most important carcinogen in cutaneous squamous cell carcinoma (SCC).1 Lower extremity (LE) SCCs, like SCCs in general, appear to be sunlight related, but SCC occurs more frequently on the head and neck and upper extremities.2-4 One striking feature of LE SCCs is that they occur more commonly in women.2-5 In clinical practice, we observe patients who have an unexpectedly high number of SCCs on their LE, who may present with significantly more SCCs on their LE compared with other sun-exposed sites. This
From the Departments of Dermatology,a and Pathology,b Yale University. Supported by a Yale University School of Medicine Research Fellowship. Conflicts of interest: None declared. Accepted for publication September 12, 2013. Reprints not available from the authors.
70
Abbreviations used: BCC: LE: MCS: SCC: UV:
basal cell carcinoma lower extremity Mohs microscopically controlled surgery squamous cell carcinoma ultraviolet
pattern of tumor occurrence may suggest that SCCs of the LE could represent a distinct subset of SCCs. We sought to evaluate these clinical observations by characterizing a patient population with increased SCCs of the LE.
Correspondence to: David J. Leffell, MD, Department of Dermatology, Section of Dermatologic Surgery and Cutaneous Oncology, Yale University, 333 Cedar St, PO Box 208059, New Haven, CT 06520. E-mail: [email protected]. Published online November 7, 2013. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.09.026
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were on the LEs; 74 SCCs in situ, of which 33 (44.6%) were on the LEs; 54 BCCs, of which 11 (20.4%) The medical records of all patients seen in the were on the LE. During the study period, the Section of Dermatologic Surgery and Cutaneous patient with the greatest number of SCCs had a Oncology at Yale School of Medicine who were total of 55 of which 33 were on the LE. The median given a diagnosis of SCC on their LE (thigh, shin, calf, number of SCCs on a patient during the study period knee, ankle, foot, leg) during the 4.5-year period was 11.5. The subjects in our study developed from January 1, 2008, to June 30, 2012, were between 34.8% to 100% of reviewed. The study was aptheir SCCs on their LE. proved by the Institutional CAPSULE SUMMARY Figs 1 to 3 summarize in Review Board of the Yale detail the anatomic distribuSchool of Medicine. We inLower extremity squamous cell tion of biopsy-diagnosed cluded those patients who carcinomas (SCCs) occur mostly in SCCs, SCCs in situ, and BCCs. had at least 4 biopsy-proven females. The anterior aspect of the diagnoses of SCCs (including A subset of patients with multiple lower LE had 1.51 times more SCCs SCC of the keratoacanthoma extremity SCCs develop these lesions in compared with the posterior subtype but excluding SCC excess of SCC and basal cell carcinoma aspect of the LE, as judged by in situ) on their LE. We on other anatomic locations. biopsy location descriptions excluded patients who in dermatopathology rewere immunocompromised ports. Lesions that were on (organ transplant recipient, the foot, or documented as neither front or back HIV positive) or were undergoing UV radiation were not included in this analysis. therapy for psoriasis. In all, 22 patients met our Of the 275 LE SCCs where the treatment could inclusion criteria. The following data were extracted be confirmed, 112 were not treated beyond and maintained in a standard database software the original biopsy. In 105 of these cases, the application (Excel, Microsoft, Redmond, WA): patangential biopsy at the clinical base of the lesion tient age, gender, family history of skin cancer, served as excision of the lesion and was usually medical history of skin cancer, and smoking history. combined with electrodessication with the intention The body site, biopsy date, treatment method, treatof completely treating the lesion. In 4 cases, ment date, size, and histopathologic characteristics Mohs microscopically controlled surgery (MCS) including presence of perineural and/or intravascuwas performed on a clinically diagnosed SCC for lar invasion were also recorded. Physician notes, which initial biopsy had not been performed. In 3 pathology reports, and photographs where neceslesions, MCS was scheduled but not performed after sary were used to determine the specific anatomic the biopsy as there was no residual lesion on the locations of the diagnosed skin cancers. surgery day. For statistical analysis, 1-sample Student t test Of the 163 lesions that were treated again was used to compare the mean proportion of all after the initial biopsy date, 130 received MCS, SCCs occurring on the LE with other anatomic sites and 1 received photodynamic therapy with topical 20% with basal cell carcinoma (BCC). Two-sample t test d-aminolevulinic acid, and 32 received re-excision was used to compare the mean diameters of lesions with electrodessication. The difference between the that were treated with different treatment modalities. average diameter of the LE SCCs that were treated RESULTS completely at the time of initial biopsy (11.1 mm) Patient demographics and history and those that received MCS (12.4 mm) was not Of the 22 patients (all Caucasian), 18 (82%) were significant (P = .078). MCS was curative in all cases female and 4 (18%) were male with an average age of despite the variability in the time interval between 80.5 years (SD 7.9 years, range 62-92 years). Four the initial biopsy and surgery (average: 39.9 days, SD: patients (18%) had a history of cancer other than 20.7 days, range: 7-118 days). One LE SCC (0.38%) nonmelanoma and melanoma skin cancer. Six demonstrated evidence of perineural invasion, and patients (27%) stated that they had an immediate no lesion had evidence of intravascular invasion. family member (parent, sibling, or child) with a history of skin cancer. DISCUSSION This study confirms and elaborates on a clinical Clinical features and treatment subset of SCCs and establishes that our patient In all, 22 patients accounted for 360 SCCs population developed SCCs of the LE dispropor(not including SCCs in situ), of which 260 (72.2%) tionate to the development of UV-induced skin d
d
72 Kim, Ko, and Leffell
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JANUARY 2014
Fig 1. Anatomic distribution of squamous cell carcinoma in the study subjects.
cancers of the head and neck or upper extremities. Epidemiologic studies consistently find that fewer than 10% of BCCs and SCCs occur on the LE in both men and women, whereas over 60% of BCCs and SCCs are on the head and neck region.2-4 In contrast, our patients as a whole had 72.2% of SCCs on their LE, 10 times more than the proportion they developed on the head and neck. The 18 women in our study had between 36.4% and 100% of all SCCs on the LE, and the average was statistically significantly different (P \ .001) from other published data of 7.5%.3 The 4 men in our study had between 34.8% and 100% of all SCCs on the LE, much elevated from the epidemiological data of 3.8%.3 Not all of our findings can be adequately explained by UV exposure alone. Although the high incidence of SCCs on the LE in women may be explained by clothing and lifestyle, another consideration is the impact of the use of moisturizers and cosmetics, which may increase the skin’s sensitivity to UV radiation.
The higher incidence of SCCs on the LE documented in this study strongly suggests regional anatomic variation in cutaneous susceptibility to SCCs. In our patients, SCCs occurred more frequently on the LE than BCCs: overall, 72.2% (260 of 360) of SCCs and 20.4% (11 of 54) of BCCs were on the LE. Furthermore, our patients have 6.67 times higher overall incidence of SCCs compared with BCCs, whereas BCCs are much more common than SCCs epidemiologically.2-4 This ratio is similar to that seen in immune-suppressed organ transplant recipients.6 Systemic immunosuppression has also been associated with SCCs.7 We hypothesize that local immunosuppression in the LE may be a factor in the relatively increased incidence of SCCs in this anatomic region. In support of this, BCCs and Kaposi sarcoma in a locally immunocompromised LE have been reported in the literature.8,9 In addition to local immunosuppression, other factors that may be involved include trauma or carcinogens. The lower leg, particularly the anterior surface, is prone to trauma, and SCCs have been
J AM ACAD DERMATOL VOLUME 70, NUMBER 1
Kim, Ko, and Leffell 73
Fig 2. Anatomic distribution of squamous cell carcinoma in situ in study subjects.
associated with sites of injury.10 Trauma could explain the predominance of SCCs on the front of the leg versus the back of the leg. In addition, the anterior surface of the leg may receive more sun exposure in patients who lie supine to tan frequently thus increasing both local UVB-induced immune suppression and UV-induced genetic changes disposing to the development of SCCs in excess of BCCs. SCCs of the LE in our study are not particularly aggressive. The time gap between the initial biopsy and MCS varied from 7 to 118 days but that did not affect prognosis. There was no statistically significant size difference between the LE SCCs that were treated at the time of initial biopsy (removal by excision at base of lesion with electrodessication) alone and those that received additional treatment after the biopsy date. We believe that SCCs of the LE represent a specific clinical subset of SCCs. Our patients have patterns of skin cancer presentation that deviate in some important ways from data already published: SCCs are more than 6 times more common than BCCs in
our patients, a complete reversal of the pattern in the population at large; SCCs in the current study show much greater tendency to occur on the LE than BCCs. Further study is underway to determine the genotypic characteristics of the LE SCCs both within the particular patient and across the patient population. Analysis of the biology of local immune function may also help explain the cause and behavior of LE SCCs.
REFERENCES 1. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, et al. Sunburn and p53 in the onset of skin cancer. Nature 1994;372:773-6. 2. Armstrong BK, Kricker A. The epidemiology of UV-induced skin cancer. J Photochem Photobiol B 2001;63:8-18. 3. Osterlind A, Hou-Jensen K, Møller Jensen O. Incidence of cutaneous malignant melanoma in Denmark 1978-1982: anatomic site distribution, histologic types, and comparison with non-melanoma skin cancer. Br J Cancer 1988;58:385-91. 4. Gallagher RP, Ma B, McLean DI, Yang CP, Ho V, Carruthers JA, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 1990;23:413-21.
J AM ACAD DERMATOL
74 Kim, Ko, and Leffell
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Fig 3. Anatomic distribution of basal cell carcinoma in the study subjects. 5. McCall CO, Chen SC. Squamous cell carcinoma of the legs in African Americans. J Am Acad Dermatol 2002;47:524-9. 6. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-20. 7. Iannacone MR, Wang W, Stockwell HG, O’Rourke K, Giuliano AR, Sondak VK, et al. Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skinea case-control study. BMC Cancer 2012;12:417.
8. Ruocco V, Satriano RA. Basal cell cancer and classic Kaposi’s sarcoma in a locally immunocompromised patient. Int J Dermatol 1986;25:594-6. 9. Ruocco V, Astarita C, Guerrera V, Lo Schiavo A, Moscariello CG, Satriano RA, et al. Kaposi’s sarcoma on a lymphedematous immunocompromised limb. Int J Dermatol 1984;23:56-60. 10. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K, et al. In: Fitzpatrick’s dermatology in general medicine. 8th ed. New York: McGraw-Hill; 2008.
E
nvironmental ultraviolet (UV) radiation has been widely acknowledged as the single most important carcinogen in cutaneous squamous cell carcinoma (SCC).1 Lower extremity (LE) SCCs, like SCCs in general, appear to be sunlight related, but SCC occurs more frequently on the head and neck and upper extremities.2-4 One striking feature of LE SCCs is that they occur more commonly in women.2-5 In clinical practice, we observe patients who have an unexpectedly high number of SCCs on their LE, who may present with significantly more SCCs on their LE compared with other sun-exposed sites. This
From the Departments of Dermatology,a and Pathology,b Yale University. Supported by a Yale University School of Medicine Research Fellowship. Conflicts of interest: None declared. Accepted for publication September 12, 2013. Reprints not available from the authors.
70
Abbreviations used: BCC: LE: MCS: SCC: UV:
basal cell carcinoma lower extremity Mohs microscopically controlled surgery squamous cell carcinoma ultraviolet
pattern of tumor occurrence may suggest that SCCs of the LE could represent a distinct subset of SCCs. We sought to evaluate these clinical observations by characterizing a patient population with increased SCCs of the LE.
Correspondence to: David J. Leffell, MD, Department of Dermatology, Section of Dermatologic Surgery and Cutaneous Oncology, Yale University, 333 Cedar St, PO Box 208059, New Haven, CT 06520. E-mail: [email protected]. Published online November 7, 2013. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.09.026
J AM ACAD DERMATOL
Kim, Ko, and Leffell 71
VOLUME 70, NUMBER 1
METHODS
were on the LEs; 74 SCCs in situ, of which 33 (44.6%) were on the LEs; 54 BCCs, of which 11 (20.4%) The medical records of all patients seen in the were on the LE. During the study period, the Section of Dermatologic Surgery and Cutaneous patient with the greatest number of SCCs had a Oncology at Yale School of Medicine who were total of 55 of which 33 were on the LE. The median given a diagnosis of SCC on their LE (thigh, shin, calf, number of SCCs on a patient during the study period knee, ankle, foot, leg) during the 4.5-year period was 11.5. The subjects in our study developed from January 1, 2008, to June 30, 2012, were between 34.8% to 100% of reviewed. The study was aptheir SCCs on their LE. proved by the Institutional CAPSULE SUMMARY Figs 1 to 3 summarize in Review Board of the Yale detail the anatomic distribuSchool of Medicine. We inLower extremity squamous cell tion of biopsy-diagnosed cluded those patients who carcinomas (SCCs) occur mostly in SCCs, SCCs in situ, and BCCs. had at least 4 biopsy-proven females. The anterior aspect of the diagnoses of SCCs (including A subset of patients with multiple lower LE had 1.51 times more SCCs SCC of the keratoacanthoma extremity SCCs develop these lesions in compared with the posterior subtype but excluding SCC excess of SCC and basal cell carcinoma aspect of the LE, as judged by in situ) on their LE. We on other anatomic locations. biopsy location descriptions excluded patients who in dermatopathology rewere immunocompromised ports. Lesions that were on (organ transplant recipient, the foot, or documented as neither front or back HIV positive) or were undergoing UV radiation were not included in this analysis. therapy for psoriasis. In all, 22 patients met our Of the 275 LE SCCs where the treatment could inclusion criteria. The following data were extracted be confirmed, 112 were not treated beyond and maintained in a standard database software the original biopsy. In 105 of these cases, the application (Excel, Microsoft, Redmond, WA): patangential biopsy at the clinical base of the lesion tient age, gender, family history of skin cancer, served as excision of the lesion and was usually medical history of skin cancer, and smoking history. combined with electrodessication with the intention The body site, biopsy date, treatment method, treatof completely treating the lesion. In 4 cases, ment date, size, and histopathologic characteristics Mohs microscopically controlled surgery (MCS) including presence of perineural and/or intravascuwas performed on a clinically diagnosed SCC for lar invasion were also recorded. Physician notes, which initial biopsy had not been performed. In 3 pathology reports, and photographs where neceslesions, MCS was scheduled but not performed after sary were used to determine the specific anatomic the biopsy as there was no residual lesion on the locations of the diagnosed skin cancers. surgery day. For statistical analysis, 1-sample Student t test Of the 163 lesions that were treated again was used to compare the mean proportion of all after the initial biopsy date, 130 received MCS, SCCs occurring on the LE with other anatomic sites and 1 received photodynamic therapy with topical 20% with basal cell carcinoma (BCC). Two-sample t test d-aminolevulinic acid, and 32 received re-excision was used to compare the mean diameters of lesions with electrodessication. The difference between the that were treated with different treatment modalities. average diameter of the LE SCCs that were treated RESULTS completely at the time of initial biopsy (11.1 mm) Patient demographics and history and those that received MCS (12.4 mm) was not Of the 22 patients (all Caucasian), 18 (82%) were significant (P = .078). MCS was curative in all cases female and 4 (18%) were male with an average age of despite the variability in the time interval between 80.5 years (SD 7.9 years, range 62-92 years). Four the initial biopsy and surgery (average: 39.9 days, SD: patients (18%) had a history of cancer other than 20.7 days, range: 7-118 days). One LE SCC (0.38%) nonmelanoma and melanoma skin cancer. Six demonstrated evidence of perineural invasion, and patients (27%) stated that they had an immediate no lesion had evidence of intravascular invasion. family member (parent, sibling, or child) with a history of skin cancer. DISCUSSION This study confirms and elaborates on a clinical Clinical features and treatment subset of SCCs and establishes that our patient In all, 22 patients accounted for 360 SCCs population developed SCCs of the LE dispropor(not including SCCs in situ), of which 260 (72.2%) tionate to the development of UV-induced skin d
d
72 Kim, Ko, and Leffell
J AM ACAD DERMATOL
JANUARY 2014
Fig 1. Anatomic distribution of squamous cell carcinoma in the study subjects.
cancers of the head and neck or upper extremities. Epidemiologic studies consistently find that fewer than 10% of BCCs and SCCs occur on the LE in both men and women, whereas over 60% of BCCs and SCCs are on the head and neck region.2-4 In contrast, our patients as a whole had 72.2% of SCCs on their LE, 10 times more than the proportion they developed on the head and neck. The 18 women in our study had between 36.4% and 100% of all SCCs on the LE, and the average was statistically significantly different (P \ .001) from other published data of 7.5%.3 The 4 men in our study had between 34.8% and 100% of all SCCs on the LE, much elevated from the epidemiological data of 3.8%.3 Not all of our findings can be adequately explained by UV exposure alone. Although the high incidence of SCCs on the LE in women may be explained by clothing and lifestyle, another consideration is the impact of the use of moisturizers and cosmetics, which may increase the skin’s sensitivity to UV radiation.
The higher incidence of SCCs on the LE documented in this study strongly suggests regional anatomic variation in cutaneous susceptibility to SCCs. In our patients, SCCs occurred more frequently on the LE than BCCs: overall, 72.2% (260 of 360) of SCCs and 20.4% (11 of 54) of BCCs were on the LE. Furthermore, our patients have 6.67 times higher overall incidence of SCCs compared with BCCs, whereas BCCs are much more common than SCCs epidemiologically.2-4 This ratio is similar to that seen in immune-suppressed organ transplant recipients.6 Systemic immunosuppression has also been associated with SCCs.7 We hypothesize that local immunosuppression in the LE may be a factor in the relatively increased incidence of SCCs in this anatomic region. In support of this, BCCs and Kaposi sarcoma in a locally immunocompromised LE have been reported in the literature.8,9 In addition to local immunosuppression, other factors that may be involved include trauma or carcinogens. The lower leg, particularly the anterior surface, is prone to trauma, and SCCs have been
J AM ACAD DERMATOL VOLUME 70, NUMBER 1
Kim, Ko, and Leffell 73
Fig 2. Anatomic distribution of squamous cell carcinoma in situ in study subjects.
associated with sites of injury.10 Trauma could explain the predominance of SCCs on the front of the leg versus the back of the leg. In addition, the anterior surface of the leg may receive more sun exposure in patients who lie supine to tan frequently thus increasing both local UVB-induced immune suppression and UV-induced genetic changes disposing to the development of SCCs in excess of BCCs. SCCs of the LE in our study are not particularly aggressive. The time gap between the initial biopsy and MCS varied from 7 to 118 days but that did not affect prognosis. There was no statistically significant size difference between the LE SCCs that were treated at the time of initial biopsy (removal by excision at base of lesion with electrodessication) alone and those that received additional treatment after the biopsy date. We believe that SCCs of the LE represent a specific clinical subset of SCCs. Our patients have patterns of skin cancer presentation that deviate in some important ways from data already published: SCCs are more than 6 times more common than BCCs in
our patients, a complete reversal of the pattern in the population at large; SCCs in the current study show much greater tendency to occur on the LE than BCCs. Further study is underway to determine the genotypic characteristics of the LE SCCs both within the particular patient and across the patient population. Analysis of the biology of local immune function may also help explain the cause and behavior of LE SCCs.
REFERENCES 1. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, et al. Sunburn and p53 in the onset of skin cancer. Nature 1994;372:773-6. 2. Armstrong BK, Kricker A. The epidemiology of UV-induced skin cancer. J Photochem Photobiol B 2001;63:8-18. 3. Osterlind A, Hou-Jensen K, Møller Jensen O. Incidence of cutaneous malignant melanoma in Denmark 1978-1982: anatomic site distribution, histologic types, and comparison with non-melanoma skin cancer. Br J Cancer 1988;58:385-91. 4. Gallagher RP, Ma B, McLean DI, Yang CP, Ho V, Carruthers JA, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 1990;23:413-21.
J AM ACAD DERMATOL
74 Kim, Ko, and Leffell
JANUARY 2014
Fig 3. Anatomic distribution of basal cell carcinoma in the study subjects. 5. McCall CO, Chen SC. Squamous cell carcinoma of the legs in African Americans. J Am Acad Dermatol 2002;47:524-9. 6. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-20. 7. Iannacone MR, Wang W, Stockwell HG, O’Rourke K, Giuliano AR, Sondak VK, et al. Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skinea case-control study. BMC Cancer 2012;12:417.
8. Ruocco V, Satriano RA. Basal cell cancer and classic Kaposi’s sarcoma in a locally immunocompromised patient. Int J Dermatol 1986;25:594-6. 9. Ruocco V, Astarita C, Guerrera V, Lo Schiavo A, Moscariello CG, Satriano RA, et al. Kaposi’s sarcoma on a lymphedematous immunocompromised limb. Int J Dermatol 1984;23:56-60. 10. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K, et al. In: Fitzpatrick’s dermatology in general medicine. 8th ed. New York: McGraw-Hill; 2008.
