Rates of cutaneous metastases from different internal malignancies: Experience from a Taiwanese medical center

ORIGINAL

ARTICLES

Rates of cutaneous metastases from different internal malignancies: Experience from a Taiwanese medical center Stephen Chu-Sung Hu, MBBS, MPhil,a Gwo-Shing Chen, MD, PhD,a,b Ching-Shuang Wu, PhD,c Chee-Yin Chai, MD, PhD,d Wan-Tzu Chen, MS,d and Cheng-Che E. Lan, MD, PhDa,b Kaohsiung, Taiwan Background: Previous reports regarding the rates at which various internal tumors metastasize to the skin have been limited and have only included the Caucasian population. Moreover, the mechanisms that predispose certain internal malignancies to metastasize to the skin have rarely been discussed in the scientific literature. Objectives: We determined the frequencies with which various internal malignancies metastasize to the skin in patients from a Taiwanese medical center. We also evaluated whether expressions of chemokine receptors CCR10 and CXCR4 by tumor cells correlate with cutaneous metastatic ability. Methods: Clinical records from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, during 20 years (1986-2006) were reviewed and cases of biopsy-proven primary internal malignancies and cutaneous metastases were identified. Immunohistochemical staining with antibodies to CCR10 and CXCR4 was performed on a selected number of internal malignancies with and without skin metastases. Results: From 12,146 patients with internal malignancies, we found 124 cases (1.02%) with cutaneous metastases. The highest rates of skin metastases were found to occur from carcinoma of the breast, followed by the lung, oral mucosa, colon and rectum, stomach, and esophagus. However, the rate of cutaneous metastasis from breast cancer was much lower compared with previous studies involving Caucasians. In general, adenocarcinomas gave rise to cutaneous metastases at a higher frequency compared with other histologic subtypes. In addition, the expressions of CCR10 and CXCR4 by tumor cells did not correlate well with the presence or absence of skin metastases. Limitation: This study is retrospective in nature. Conclusions: Different internal malignancies metastasize to the skin with different frequencies, and the rates at which different malignancies metastasize to cutaneous sites differ between the Taiwanese and Caucasian populations. The mechanisms responsible for the cutaneous metastatic ability of certain malignancies likely involve factors other than chemokine receptors CCR10 and CXCR4, because their expressions by tumor cells are neither necessary nor sufficient for the formation of skin metastases. ( J Am Acad Dermatol 2009;60:379-87.)

utaneous involvement by internal malignancies is uncommon and has been estimated to occur in 0.7% to 9% of patients with internal cancers.1-10 Skin infiltration by cancer

C

can occur by several different pathways: hematogenous, lymphatic, direct contiguous tissue invasion, and iatrogenic implantation.3,11 Only the first two pathways have been widely regarded to represent

From the Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical Universitya; Department of Dermatology, College of Medicine, Kaohsiung Medical Universityb; Faculty of Biomedical Laboratory Science, Kaohsiung Medical Universityc; and Department of Pathology, Kaohsiung Medical University Hospital.d Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 2, 2008.

Reprint requests: Cheng-Che E. Lan, MD, PhD, Department of Dermatology, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. E-mail: ec_lan@ hotmail.com. Published online December 4, 2008. 0190-9622/$36.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.10.007

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true metastatic spread. Previously, there has been a very limited number of reports examining the variation in the frequencies of cutaneous metastases from different internal malignancies.1,4-6 In addition, no similar studies regarding the rates of cutaneous metastases from different internal malignancies have been performed on the East Asian (Chinese, Taiwanese, Japanese, Korean) population, despite racial differences in biologic characteristics of various cancers between East Asian groups and Caucasians. The mechanisms that predispose certain internal malignancies to give rise to cutaneous metastases have rarely been discussed in the scientific literature. Recently, chemokines and their receptors have been shown to mediate tumorigenesis and metastasis. The chemokine receptor CCR10 has been found to be involved in cutaneous metastasis of melanomas, by mediating migration, survival, and growth of melanoma cells at cutaneous sites.12-15 The CCR10 ligand CCL27/CTACK is a skin-specific chemokine that is constitutively expressed by epidermal keratinocytes.16,17 Therefore, the interaction between CCR10 on tumor cells and CCL27/CTACK from the epidermis may mediate colonization of melanoma cells at cutaneous sites. In addition, the chemokine receptor CXCR4 has been shown to be important in the growth, angiogenesis, and invasion of cutaneous basal cell carcinomas,18,19 and plays a role in the skin-homing mechanism of Se´zary cells.20 Its ligand, stromal-cell-derived factor-1a/CXCL12, is constitutively expressed by dermal fibroblasts and endothelial cells.21,22 It is, therefore, possible that CCR10 and CXCR4 may be involved in the preferential ability of certain cancer cells to metastasize to the skin. Previously, we have described the clinical and prognostic characteristics of 141 cases of cutaneous metastases in a Taiwanese medical center.23 In this study, we determined the rates at which different internal malignancies give rise to cutaneous metastases and compared them with previous studies involving the Caucasian population. In addition, we attempted to evaluate whether the chemokine receptors CCR10 and CXCR4 play a role in the preferential ability of certain types of internal malignancies to metastasize to cutaneous sites.

METHODS Determination of rates of cutaneous metastases from different internal malignancies This was a retrospective, nonautopsy study examining the rates of cutaneous metastases from various internal cancers in a Taiwanese medical center population. Excluded were hematogenous

malignancies (eg, lymphoma or leukemia), melanomas, and other primary skin malignancies. The 12 cancers with the highest annual incidence in Taiwan (excluding hematologic and primary cutaneous malignancies) according to a recent survey by the Taiwanese National Department of Health were considered in this study.24 These malignancies included cancers of the colon and rectum, liver, lung, breast, oral mucosa, stomach, prostate, bladder and ureter, uterine cervix, nasopharynx, esophagus, and thyroid. A comprehensive examination of pathology records from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, during 20 years (1986-2006) was performed to identify cases of biopsy-proven internal malignancies and cutaneous metastases from internal malignancies. Cutaneous metastases were defined as cancer spreading through the bloodstream or lymphatic system to involve the skin. Cutaneous involvement by direct extension of tumor or iatrogenic implantation (eg, needle tracts or surgical incision scars) was excluded, because it does not involve tumor spread via the hematogenous or lymphatic route. No autopsies were performed. Pathological reports for all cases of primary cancers and cutaneous metastases were evaluated with regard to the histologic characteristics. Medical charts were reviewed for clinical information regarding cutaneous metastases, to determine the primary origin of the skin metastases and to ensure that skin involvement was not a result of direct extension or iatrogenic implantation. Hematogenous malignancies were excluded from this study because these malignancies are characterized by malignant cells circulating in the bloodstream and lymphatic system and, therefore, their presence in the skin is not regarded to represent true metastases. In addition, primary skin malignancies (eg, melanomas and cutaneous squamous cell carcinomas) were excluded because cutaneous metastases from these tumors cannot be considered as a form of secondary organ spread. Immunohistochemical staining of primary tumors and cutaneous metastases specimens for CCR10 and CXCR4 Paraffin sections (3 m) from a selected number of internal malignancies with and without skin metastases were dewaxed and rehydrated in a graded series of alcohols. Endogenous peroxidase was blocked by preincubation with 3% H2O2. The slides were incubated with goat antihuman CCR10 antibody (1:500 dilution) (Novus Biologicals, Littleton, CO) and mouse antihuman CXCR4 antibody (1:50 dilution) (R&D Systems, Minneapolis, MN) at room

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Table I. Rates of cutaneous metastases from different internal malignancies

Primary site

Breast Lung Oral mucosa Colon and rectum Stomach Esophagus Uterine cervix Liver Bladder and ureter Thyroid Nasopharynx Prostate Overall

No. of primary tumors

No. of cutaneous metastases

Table II. Rates of cutaneous metastases according to histologic subtype

Rate of cutaneous metastasis, %

Histologic subtype

No. of primary tumors

No. of cutaneous metastases

Rate of cutaneous metastasis, %

2110 1292 628 1973 1245 403 646 1321 911

51 23 11 16 10 3 2 4 2

2.42 1.78 1.75 0.81 0.80 0.74 0.31 0.30 0.22

Adenocarcinoma Squamous cell carcinoma Hepatocellular carcinoma Transitional cell carcinoma Others and unspecified Overall

496 609 512 12,146

1 1 0 124

0.20 0.16 0.00 1.02

*Primary origin: breast (50 cases), lung (16), colon and rectum (16), stomach (10), esophagus (1), uterine cervix (1), thyroid (1). y Primary origin: lung (5 cases), oral mucosa (9), esophagus (2), uterine cervix (1).

temperature for 90 minutes. Bound antibodies were detected with biotinylated secondary antibody (Dako Corp, Carpinteria, CA) for 15 minutes at room temperature, followed by incubation with streptavidin-horseradish peroxidase (Dako) for 15 minutes at room temperature. The immunoreactivity was visualized using 3,3’-diaminobenzidine substrate-chromogen solution (Dako).

RESULTS Rates of cutaneous metastases from different internal malignancies The cumulative incidence of various pathologyproven primary internal malignancies diagnosed in our hospital (1986-2006) was determined and compared with the incidence of cutaneous metastases from different internal malignancies during the same time period (Table I). From 12,146 patients with internal malignancies, we found 124 cases with cutaneous metastases (overall metastatic rate 1.02%). Variations exist between different internal malignancies with regard to the rate of cutaneous metastases. Carcinomas of the breast, lung, and oral mucosa metastasized to the skin at relatively high frequencies; carcinomas of the colon and rectum, stomach, and esophagus metastasized to the skin with intermediate frequencies; carcinomas of the uterine cervix, liver, bladder and ureter, thyroid, nasopharynx, and prostate metastasized to the skin at very low rates. Rates of cutaneous metastases according to histologic subtype The cumulative incidence of various histologic subtypes of primary internal malignancies diagnosed

6495 2464

95* 17y

1.46 0.69

1189

4

0.34

865

2

0.23

1133

6

0.53

12,146

124

1.02

Table III. Rates of cutaneous metastases from different histologic subtypes of lung cancer

Histologic subtype

Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Bronchioloalveolar carcinoma Large cell carcinoma Others and unspecified Overall

Cutaneous metastasis from lung cancer (No. of cases)

Rate of cutaneous metastasis, %

542 430

16 5

2.95 1.16

123

1

0.81

52

0

0.00

24

0

0.00

121

1

0.83

1292

23

1.78

Primary lung cancer (No. of cases)

in our hospital (1986-2006) was determined, and compared with the incidence of various histologic subtypes for cutaneous metastases during the same time period. Our results showed that adenocarcinomas had the highest rate of skin metastases (1.46%), followed by squamous cell carcinomas (0.69%), hepatocellular carcinoma (0.34%), and transitional cell carcinoma (0.23%) (Table II). Rates of cutaneous metastases from different histologic subtypes of lung cancer Lung cancer is characterized by a mixture of histologic subtypes, including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma.

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Fig 1. Immunohistochemical staining with CCR10. Representative sections of primary breast cancer (positive staining) (A), cutaneous metastasis from breast cancer (positive staining) (B), primary lung cancer (negative staining) (C), and cutaneous metastasis from lung cancer (negative staining) (D). (Original magnifications: A and C, 340; B and D, 320.)

This is in contrast to other common cancers, which show a more uniform histologic pattern (eg, breast cancers, which are mostly adenocarcinomas). The incidences of the various histologic subtypes of primary lung cancer and cutaneous metastases from lung cancer in our medical center during 20 years (1986-2006) were compared. It was found that the rate of cutaneous metastasis from lung adenocarcinoma was much higher (2.95%) compared with lung squamous cell carcinoma (1.16%), small cell carcinoma (0.81%), bronchioloalveolar carcinoma (0%), and large cell carcinoma (0%) (Table III). Expressions of CCR10 and CXCR4 by malignancies with and without cutaneous metastases Immunohistochemical staining with CCR10 and CXCR4 was performed on 3 cases of breast cancer with skin metastasis (3 specimens of primary breast cancers and 3 specimens of skin metastases from these respective primary cancers), 3 cases of lung cancer with skin metastasis (3 specimens of primary lung cancers and 3 specimens of skin metastases from these respective primary cancers), 3 cases of lung cancer without skin metastasis, and one case of hepatocellular carcinoma without skin metastasis (Figs 1 and 2). Expression of CCR10 was noted

both in tumors with and without skin metastasis, and not all tumors with skin metastasis expressed CCR10 (Table IV). In addition, CXCR4 was expressed by the majority of internal malignancies, with and without skin metastasis (Table IV). Therefore, the expressions of CCR10 and CXCR4 by tumor cells did not correlate well with their cutaneous metastatic abilities.

DISCUSSION Previous reports examining the rates of cutaneous metastases in different internal malignancies have been limited and have only been performed in the Caucasian population.1,4-6 The results of these studies are presented in Table V. There are two major differences between our results and those of the other studies. First, the overall rate of cutaneous metastasis in our patient population was lower (1.02%) compared with previous reports. Second and more specifically, cancers of the breast and oral mucosa were associated with a much lower rate of skin metastasis in our Taiwanese patient population compared with Caucasians. The lower overall rate of cutaneous metastases in our study may have been caused by a number of factors. First, we included a number of malignancies known to have low frequencies of cutaneous

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Fig 2. Immunohistochemical staining with CXCR4. Representative sections of primary breast cancer (positive staining) (A), cutaneous metastasis from breast cancer (negative staining) (B), primary lung cancer (positive staining) (C), and cutaneous metastasis from lung cancer (positive staining) (D). (Original magnifications: A and C, 340; B and D, 320.)

metastasis but that have a high incidence in Taiwan (compared with Western countries), such as hepatocellular carcinoma and carcinomas of the nasopharynx and cervix. This would be expected to decrease the average rate of cutaneous metastasis in our study. Second, there are differences in study settings. Two of the previous studies (Abrams et al1 and Spencer and Helm4) were based on autopsy reports. This would likely find more cases of cutaneous metastases that were not clinically apparent, and the patient population may be composed of a higher proportion of advanced cancer cases with higher metastatic rate. However, the studies by Lookingbill et al5,6 (which also showed a higher overall rate of cutaneous metastasis) were based on tumor registry data in a university medical center, which was more comparable with our study setting. Third, we have only included pathology-proven primary internal malignancies and cutaneous metastases, and some cases of cutaneous metastases may not have been included in our study because they have not been biopsied. However, as a routine practice at this university medical center, biopsies would have been performed for most cases of clinically suggested skin metastases. Therefore, the impact of this confounder should be very small. Fourth, the exclusion of patients with direct

extension of tumor or iatrogenic implantation in our study may have been a factor for the low cutaneous metastatic rate. However, we note that cutaneous involvement as a result of direct tumor extension was also excluded in the studies by Lookingbill et al5,6 and Abrams et al1 (both showing a higher overall rate of cutaneous metastasis compared with our study), although this factor was not specifically mentioned by Spencer and Helm.4 The second major difference between our results and those of the previous studies regards the frequencies of cutaneous metastases from cancers of the breast and oral mucosa. Although cutaneous metastases from these two cancers occurred with higher frequencies relative to other internal malignancies in our patient population, the differences are much less pronounced compared with previous studies involving the Caucasian population (Table V). The rates of cutaneous metastases from breast cancer varied from 18.6% to 26.5% in previous reports, and these rates were much higher relative to other cancers. In fact, in the study by Lookingbill et al5,6 the overall cutaneous metastatic rate was only 1.84% (109/5930 cases) when breast and oral cancers were excluded from the calculation. In contrast, the frequencies of cutaneous metastases from breast and oral cancers were comparable with lung cancer and

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Table IV. Expression of CCR10 and CXCR4 by tumor cells CCR10 expression

CXCR4 expression

Primary Cutaneous Primary Cutaneous metastasis cancer metastasis Case cancer

Breast carcinoma with skin metastasis Lung carcinoma with skin metastasis Lung carcinoma without skin metastasis Hepatocellular carcinoma without skin metastasis

1 2 3

e 11 11

11 11 11

11 11 11

e 11 11

1 2 3

1 e 11

1 e e

1 11 11

11 11 11

1 2 3

e 1 11

11 11 e

1

e

11

11Strongly positive staining. 1Weakly positive staining. eNegative staining.

only slightly higher than carcinomas arising from the gastrointestinal tract in our study. One possible explanation for this phenomenon may be racial differences in biological characteristics between East Asians and Caucasians. Previous reports have shown racial differences in breast cancer characteristics in terms of survival,25-28 histologic characteristics,29-31 hormone receptor status,31-33 human epidermal growth factor receptor2/neu positivity,34,35 molecular abnormalities,36 and genetic alterations.37-40 Compared with Caucasians, studies of breast cancer in Asian-Chinese women found a lower overall incidence of breast cancer,41,42 a decreased risk of lobular carcinoma,31 lower rates of estrogen/progesterone receptorepositive tumors,31 higher rate of human epidermal growth factor receptor-2/neu positivity,34,35 differences in breast cancer susceptibility genes BRCA1/2 mutations and overall pattern of genetic alterations,37-40 differences in breast cancer risk factors,43 and differences in hormonal physiology.44 It is intriguing that the high prevalence of basal-like breast tumors with aggressive biological characteristics is associated with the poor prognosis of breast cancer in African American women, whereas the lower prevalence of this histologic subtype in Japanese women is associated with favorable prognosis.45,46 Similarly, the characteristics of oral cancer have been found to differ between Caucasians and East Asians in terms of incidence, survival, risk factors, genetic alterations,

and molecular changes.47-50 Further studies are necessary to determine whether an actual difference in biological characteristics of breast and oral cancers in Taiwanese and Caucasian patients may underlie the markedly lower rates of cutaneous metastases from these malignancies in our patient population. The elucidation of racial differences in biological characteristics in various malignancies could have important therapeutic implications, as recently demonstrated by the biological agent gefitinib, which showed greater efficacy in East Asian patients with lung cancer compared with Caucasians.51-54 In addition, Taiwan may differ from mainland China and other countries in terms of the biological characteristics of cancers. A subset of people from parts of southern Taiwan were endemically exposed to inorganic arsenic (a human carcinogen) from drinking artesian well water, which could possibly modify the biological characteristics of arsenic-induced visceral malignancies such as bladder, kidney, lung, and liver cancers.55-58 However, because Kaohsiung, Taiwan, is not itself an arsenic-endemic area and only a very small proportion of patients in our hospital came from regions with high arsenic levels in drinking water, the results of our study are unlikely to be significantly affected by chronic arsenic exposure. In this study, we also found that adenocarcinomas in general gave rise to cutaneous metastases at a higher rate compared with squamous cell carcinomas, hepatocellular carcinoma, or transitional cell carcinoma. The high rate of adenocarcinomas in cutaneous metastases may be caused in part by the large number of cutaneous metastases arising from the breast. However, we found that in lung cancer, the rate of cutaneous metastases for adenocarcinoma was higher compared with squamous cell carcinoma, despite the fact that these two histologic subtypes are considered to have similar aggressiveness and prognosis.59 The higher rate of skin metastasis from lung adenocarcinoma compared with squamous cell carcinoma and other histologic subtypes corroborated with a study by Dreizen et al60 involving 1000 patients with unresectable lung cancer. These findings suggest that adenocarcinomas in general are intrinsically different compared with other histologic subtypes in terms of the ability to metastasize to the skin. Recently, chemokines and their receptors have been shown to be important in tumorigenesis and metastasis. The chemokine receptor CCR10 has been demonstrated to be involved in cutaneous metastasis of melanomas. Besides mediating directed tumor cell migration, CCR10 also plays a role in protection from apoptosis, tumor progression, and the immune escape mechanisms of melanomas.12-15 The CCR10

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Table V. Rates of cutaneous metastases in Caucasian populations from previous studies Study Type of cancer*

Breast Oral mucosa Lung Colorectal Stomach Esophagus Overall Direct tumor extension included?

Abrams et al

1

31/167 (18.6%) Unknown 1/160 (0.6%) 8/205 (3.9%) 2/119 (1.7%) Unknown 44/1000 (4.4%) No

4

Lookingbill et al5,6

Spencer and Helm

185/699 (26.5%) 24/139 (17.3%) 60/1018 (5.9%) 27/450 (6.0%) 10/222 (4.5%) 1/117 (0.9%) 679/7518 (9.0%) Unknown

237/992 21/394 21/1223 18/772 6/535

(23.9%) (5.3%) (1.7%) (2.3%) (1.1%)y

367/7316 (5.0%) Yes

212/992 18/394 21/1223 18/772 6/535

(21.4%) (4.6%) (1.7%) (2.3%) (1.1%)y

Unknown No

*Data expressed as No. of cutaneous metastases/primary malignancies. y Data refers to esophagus and stomach combined.

ligand CCL27/CTACK is a skin-specific chemokine that is constitutively produced by epidermal keratinocytes.16,17 In addition, the chemokine receptor CXCR4 has been found to mediate growth, angiogenesis, and invasion of cutaneous basal cell carcinomas,18,19 and plays a role in the skin-homing mechanism of Se´zary cells.20 The CXCR4 ligand stromal-cell-derived factor-1a/CXCL12 is produced by dermal fibroblasts and endothelial cells.21,22 The possible involvement of CCR10 and CXCR4 in the skin colonization of visceral malignancies has not been previously investigated. Our results showed that expression of CCR10 and CXCR4 by tumor cells did not correlate well with their cutaneous metastatic abilities, and these chemokine receptors were neither necessary nor sufficient for the formation of skin metastases. Therefore, the mechanisms responsible for the cutaneous metastatic ability of certain malignancies probably involve factors other than these chemokine receptors. The molecular mechanisms underlying tumor metastasis are complex and incompletely understood. A tumor needs to detach from the primary tumor, invade and circulate in the blood or lymphatic system, extravasate, and finally survive and proliferate at the secondary site.7,61 Using in vivo videomicroscopy procedures, it has been shown that the early steps (survival in the circulation, arrest in the microcirculation, extravasation) are efficiently completed with little dependence on the metastatic ability of the cancer cells, whereas the later steps of cell survival and growth in the secondary site are inefficiently carried out with marked variation between cancer cells.62 Therefore, the rate-limiting step in the formation of metastasis appears to be the colonization of cancer cells in the secondary site. Because the vast majority of cutaneous metastases are found in the dermis, the interaction between tumor cells and dermal or epidermal factors may play a crucial role in the skin-homing mechanism of metastatic cells.

It is difficult for cancer cells to survive outside their region of origin, and metastatic cells may survive more easily if the secondary site has similar characteristics to the primary organ. The lactiferous ducts (from which most breast cancers originate) are derived from the embryonic ectoderm and are regarded as modified sweat glands.63 Because the cutaneous adnexa and lactiferous ducts have similar embryonic origins (both are ectoderm derived), the dermis may provide a favorable environment for the survival and colonization of metastatic breast carcinoma. This may provide a partial explanation for the higher rate of skin metastases of breast adenocarcinoma compared with adenocarcinomas of the gastrointestinal tract (which originate from the embryonic endoderm).63 The dermis may also provide a favorable environment for colonization of squamous cell carcinoma of the oral cavity (also derived from the embryonic ectoderm), leading to a higher rate of skin metastases compared with internal organ squamous cell carcinomas (eg, the esophagus, cervix, and nasopharynx). On the other hand, because of phenotypic differences between the cutaneous epithelium and specialized epithelial cancers (eg, hepatocellular carcinoma and transitional cell carcinoma), the dermal environment may not support the colonization and metastasis of these malignancies. In summary, different internal malignancies metastasize to the skin with different frequencies, and the rates at which different malignancies metastasize to cutaneous sites differ between the Taiwanese and Caucasian populations. Carcinomas of the breast, lung, and oral mucosa metastasized to the skin at relatively high frequencies. However, the rates of cutaneous metastases from breast and oral cancers were low compared with previous studies involving Caucasians. In general, adenocarcinomas gave rise to cutaneous metastases at a higher rate compared with other histologic subtypes. The mechanisms

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responsible for the cutaneous metastatic ability of certain malignancies may be complex and involve factors other than chemokine receptors CCR10 and CXCR4. Our study also indicates that cancers represent a heterogeneous group of diseases, and a certain type of cancer may differ in biologic characteristics between different racial populations. Although biological therapies have gained success in the management of certain cancers recently, their efficacy may vary in different patient populations. Proper profiling of the biological features of tumor cells among different racial groups may allow optimal use of these biological therapies. REFERENCES 1. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer 1950;3:74-85. 2. Reingold IM. Cutaneous metastases from internal carcinoma. Cancer 1966;19:162-8. 3. Rosen T. Cutaneous metastases. Med Clin North Am 1980;64: 885-900. 4. Spencer PS, Helm TN. Skin metastases in cancer patients. Cutis 1987;39:119-21. 5. Lookingbill DP, Spangler N, Sexton FM. Skin involvement as the presenting sign of internal carcinoma: a retrospective study of 7316 cancer patients. J Am Acad Dermatol 1990;22:19-26. 6. Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in patients with metastatic carcinoma: a retrospective study of 4020 patients. J Am Acad Dermatol 1993;29:228-36. 7. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol 1995;33:161-82. 8. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a metaanalysis of data. South Med J 2003;96:164-7. 9. Mueller TJ, Wu H, Greenberg RE, Hudes G, Topham N, Lessin SR, et al. Cutaneous metastases from genitourinary malignancies. Urology 2004;63:1021-6. 10. Suzuki N. Multiple skin metastases from cancer of internal organs. J Cancer Res 1918;3:357-88. 11. White JW Jr. Evaluating cancer metastatic to the skin. Geriatrics 1985;40:67-73. 12. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50-6. 13. Murakami T, Cardones AR, Hwang ST. Chemokine receptors and melanoma metastasis. J Dermatol Sci 2004;36:71-8. 14. Murakami T, Cardones AR, Finkelstein SE, Restifo NP, Klaunberg BA, Nestle FO, et al. Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med 2003;198:1337-47. 15. Simonetti O, Goteri G, Lucarini G, Filosa A, Pieramici T, Rubini C, et al. Potential role of CCL27 and CCR10 expression in melanoma progression and immune escape. Eur J Cancer 2006;42:1181-7. 16. Morales J, Homey B, Vicari AP, Hudak S, Oldham E, Hedrick J, et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci U S A 1999;96:14470-5. 17. Homey B, Wang W, Soto H, Buchanan ME, Wiesenborn A, Catron D, et al. Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skinassociated chemokine CCL27 (CTACK/ALP/ILC). J Immunol 2000;164:3465-70.

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