Cutaneous Appendageal Carcinoma Incidence and Survival Patterns in the United States a Population-Based Study

Home , Eccrine carcinoma, Hidradenocarcinoma, Sebaceous carcinoma

STUDY Cutaneous Appendageal Carcinoma Incidence and Survival Patterns in the United States A Population-Based Study

Patrick W. Blake, BS; Porcia T. Bradford, MD; Susan S. Devesa, PhD; Jorge R. Toro, MD

Objective: To examine incidence patterns of patients lower IRs than non-Hispanic whites (IR, 5.7) (PϽ.001). diagnosed as having cutaneous appendageal carcinoma Apocrine-eccrine carcinoma overall was the most (CAC). common category (IR, 2.6), and the IR was highest among non-Hispanic white (IR, 2.8) compared with other ethnic/ Design: Population-based study using the Surveil- racial groups (PϽ.001). Cutaneous appendageal carcino- lance, Epidemiology, and End Results (SEER) Program mas IRs rose 100-fold with age, from 0.37 among those of the National Cancer Institute data from 1978 through aged 20 to 29 years to 37.3 among those 80 years or older. 2005. From 1978-1982 to 2002-2005, the CAC IRs increased 150%, from 2.0 to 5.0; the apocrine-eccrine carcinoma and Participants: A total of 1801 subjects from SEER 16 reg- the sebaceous carcinoma IRs rose 170%, from 1.0 to 2.7, istries (2001-2005) for incidence analyses, 2228 from and 217%, from 0.6 to 1.9, respectively. Five-year rela- SEER 9 registries (1987-2005) for trend analysis, and 1984 subjects (1992-2004) for survival analysis. tive survival rates overall were 99% for localized and 43% for distant disease. Main Outcome Measure: Incidence rates (IRs) per 1 million person-years according to anatomic site, race, sex, Conclusions: Cutaneous appendageal carcinomas are rare age, and histologic type. tumors with IRs that vary by sex and racial/ethnic group. Cutaneous appendageal carcinoma IRs are increasing in Results: Cutaneous appendageal carcinomas are uncom- the United States, especially for sebaceous carcinoma, per- mon (age-adjusted IR, 5.1 per 1 million person-years), with haps related to improved recognition and classification, the IR among men statistically significantly higher than but factors such as UV exposure and immunosuppres- women (6.3 vs 4.2, respectively; male to female IR ratio sion may also play a role. 1.51; PϽ.001). Hispanic whites (IR, 3.7), blacks (IR, 3.5), and Asian/Pacific Islanders (IR, 2.5) all had significantly Arch Dermatol. 2010;146(6):625-632

UTANEOUS APPENDAGEAL text of inherited cancer syndromes such carcinomas (CACs) are a as sebaceous carcinoma in Muir-Torre rare and diverse group of syndrome5 and spiradenocarcinoma in complex neoplasms with Brooke-Spiegler syndrome.6 Although the diverse differentiation that epidemiological patterns of sebaceous car- 7,8 Author Affiliations: Genetic frequentlyC represent a diagnostic chal- cinoma have been reported, the epide- Epidemiology Branch (Mr Blake lenge. Cutaneous appendageal carcino- miological patterns of other CACs are and Drs Bradford and Toro) and mas were recently categorized according mostly unknown.1 Biostatistics Branch to the 2005 World Health Organization Studies of CACs have been limited be- (Dr Devesa), Division of Cancer (WHO) classification of skin carcino- cause of their rarity and thus the inability Epidemiology and Genetics, 1 National Cancer Institute, mas. This consensus classification takes to study large numbers of patients. To date, 9 National Institutes of Health, into account the distinct clinical, histo- only 62 cases of spiradenocarcinoma and Department of Health and logical, and molecular genetic features and adenoid cystic carcinoma10 and less than 100 Human Services, Bethesda, includes 3 main types of differentiation: cases of most other apocrine-eccrine car- Maryland; Howard Hughes apocrine-eccrine, follicular, and seba- cinomas (hidradenocarcinoma, apocrine Medical Institute–National ceous.1 Most of these cutaneous carcino- carcinoma, digital papillary carcinoma, Institutes of Health Research Scholars Program, Bethesda mas present de novo, although they can and malignant mixed tumor) have been (Mr Blake); and Department of arise in precursor lesions such as nevus reported in the English language litera- 9-14 Veterans Affairs Medical Center, sebaceous or in a pre-existing benign coun- ture. Approximately 200 mucinous car- Washington, DC (Dr Toro). terpart.2-4 They can also occur in the con- cinoma, 300 porocarcinoma, and micro-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Cutaneous Appendageal Carcinomas Diagnosed During 2001 Through 2005 in the Seer 16 Program Registries18 by Histologic Type and Sexa

Sex

Median Total By Type M F Age at ICD-O-3 Diagnosis, Cases, Freq, Freq, Rate Cases, Rate Cases, Rate M:F IRR Histologic Type Codes y No. % % (95% CI)b No. (95% CI)b No. (95% CI)b (95% CI) Total 70 1801 100 5.1 (4.8-5.3) 966 6.3 (5.9-6.7) 835 4.2 (3.9-4.5) 1.51 (1.38-1.66) Apocrine-eccrine carcinomas 68 926 51.4 100 2.6 (2.4-2.8) 456 2.9 (2.7-3.2) 470 2.4 (2.2-2.6) 1.24 (1.08-1.41) Adenoid cystic carcinoma 8200 61 76 4.2 8.2 0.2 (0.2-0.3) 35 0.2 (0.1-0.3) 41 0.2 (0.2-0.3) 1.02 (0.63-1.65) Hidradenocarcinoma 8400, 8402 68 154 8.1 16.6 0.4 (0.4-0.5) 84 0.5 (0.4-0.7) 70 0.4 (0.3-0.4) 1.53 (1.10-2.14) Microcystic adnexal 8407 68 228 12.7 24.6 0.6 (0.6-0.7) 95 0.6 (0.5-0.8) 133 0.7 (0.6-0.8) 0.93 (0.70-1.22) carcinoma Porocarcinoma 8409 75 126 7.0 13.6 0.4 (0.3-0.4) 79 0.5 (0.4-0.7) 47 0.2 (0.2-0.3) 2.34 (1.60-3.43) Eccrine carcinoma 8413 68.5 139 7.7 15.0 0.4 (0.3-0.5) 67 0.4 (0.3-0.5) 72 0.4 (0.3-0.5) 1.19 (0.84-1.69) Mucinous carcinoma 8480 69 80 4.4 8.6 0.2 (0.2-0.3) 28 0.2 (0.1-0.2) 52 0.3 (0.2-0.3) 0.63 (0.38-1.01) Other apocrine-eccrine 62 123 6.8 13.3 0.3 (0.3-0.4) 68 0.4 (0.3-0.5) 55 0.3 (0.2-0.4) 1.51 (1.04-2.20) carcinomas Apocrine carcinoma 8401 66 56 3.1 6.0 0.2 (0.1-0.2) 28 0.2 (0.1-0.3) 28 0.1 (0.1-0.2) 1.25 (0.71-2.19) Spiradenocarcinoma 8403 66 26 1.4 2.8 0.1 (0-0.1) 16 0.1 (0.1-0.2) 10 0 (0-0.1) 2.26 (0.95-5.58) Digital papillary 8408 48.5 24 1.3 2.6 0.1 (0-0.1) 19 0.1 (0.1-0.2) 5 NR NR carcinoma Malignant mixed 8940 57 17 0.9 1.8 0 (0-0.1) 5 NR 12 0.1 (0-0.1) NR tumor Sebaceous carcinoma 8410 72 629 34.9 100 1.8 (1.6-1.9) 358 2.4 (2.1-2.6) 271 1.3 (1.2-1.5) 1.76 (1.50-2.07) Skin appendage 8390 72.5 246 13.7 100 0.7 (0.6-0.8) 152 1.0 (0.9-1.2) 94 0.5 (0.4-0.6) 2.21 (1.69-2.90) carcinoma, NOS

Abbreviations: CI, confidence interval; Freq, frequency; ICD-O-3, International Classification of Diseases for Oncology, Third Edition ; IRR, incidence rate ratio; NOS, not otherwise specified; NR, not reported (statistic not presented owing to less than 10 cases); SEER, Surveillance, Epidemiology, and End Results. a Excludes Alaska registry and American Indian, Alaska Native, and unknown/other race. b Rates are per 1 million person-years and age-adjusted to the 2000 US standard population (19 age groups20).

cystic adnexal carcinoma cases have been published in the registry, and cases with race coded as “unknown” were ex- literature as case reports or clinical series.15-17 To date, popu- cluded. Quality control efforts include review of case finding, lation-based studies of CACs overall and by histological reabstracting, and recoding. The SEER registries records the subtypes have not been conducted except for sebaceous primary site of the carcinoma and do not collect data regard- carcinoma7,8 and mucinous carcinoma.15 Since the etiol- ing metastatic sites. Cases were identified using the World Health Organization’s International Classification of Diseases for On- ogy of these carcinomas remains largely unknown, com- cology, Third Edition (ICD-O-3) codes for cutaneous appenda- parison of epidemiological patterns for specific subtypes geal tumors.19 The main analyses focused on cases diagnosed may elucidate important clues for future studies. In this during 2001 through 2005 (Table 1), when ICD-O-3 codes study, we conducted the first comprehensive and largest were used, reflecting the most current and relevant codes. Codes analysis, to our knowledge, of incidence rates (IRs) and with less than 10 total carcinoma cases (8110, pilomatrix car- relative survival rates (SRs) in the US population-based Sur- cinoma; 8211, tubular adenocarcinoma; 8406, papillary syrin- veillance, Epidemiology and End Results (SEER) pro- goadenocarcinoma; 8481, adenocarcinoma; and 8941, carci- gram of the National Cancer Institute (NCI) according to noma in pleomorphic adenoma) and codes representing Paget patient demographic characteristics and histologic types, (code 8540) and extramammary Paget (code 8542) disease were using the 2005 WHO classification.1 excluded. The remaining cases with ICD-O-3 morphology codes (8390, 8200, 8400-8403, 8407-8410, 8413, 8480, and 8940) that included a primary skin site code (C440-C449) were in- METHODS cluded in this study. We grouped individual 4-digit histology codes into 3 major histologic types. Population-based cancer frequency, incidence, and survival data Age-adjusted (2000 US standard) IRs were calculated using were evaluated for cutaneous appendageal cases diagnosed the SEER*Stat software public use program version 6.5121; IRs among residents of SEER 16 program registries.18 The 16 reg- were expressed as new cases per 1 million person-years and were istries include 8 states (Connecticut, Hawaii, Iowa, Kentucky, analyzed by age, sex, race, ethnicity, and year of diagnosis. Tem- Louisiana, New Jersey, New Mexico, and Utah), greater Cali- poral trend analyses were conducted for those categories that have fornia, rural Georgia, and 6 metropolitan areas (Atlanta, Geor- been recognized long-term, using data from 1978 through 2005 gia; Detroit, Michigan; Los Angeles, San Francisco-Oakland, from the original SEER 9 registries (2228 subjects). Temporal and San Jose-Monterey, California; and Seattle-Puget Sound, trends and age-specific rates were plotted using a semilog scale, Washington). During 2000, the populations in the SEER 16 reg- with a y- to x-axis ratio of 1 log cycle=40 years, such that an istries represented approximately 26% of the US population, angle of 10° portrayed a change of 1% per year.22 We aggregated including 25% of US whites, 23% of US African Americans, 54% data over years to derive more stable rate estimates. Differences of US Asians/Pacific Islanders, and 40% of US Hispanics. Case in rates and ratios of rates and confidence intervals (CIs) were counts, population estimates, and IRs for Louisiana for only calculated using SEER*Stat version 6.5.1. Following SEER con- the first 6 months of 2005 were used, so that no further ad- ventions, 5-year relative SRs for cases diagnosed during 1992 justments for the effects of Hurricanes Katrina and Rita were through 1999 in the SEER 12 registries and during 2000 through necessary. Data for American Indians/Alaska Natives, the Alaska 2004 in the SEER 16 registries were calculated using the actu-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2. Cutaneous Appendageal Carcinomas Diagnosed During 2001 Through 2005 in the SEER 16 Program Registries18 by Histologic Type and Race/Ethnicitya

NHW HW Black A/PI IRR (95% CI)

Rateb Rate Rate Rate Histologic Type Cases (95% CI) Casesc (95% CI) Cases (95% CI) Cases (95% CI) HW:NHW Black:NHW A/PI:NHW Total 1473 5.7 (5.4-6.0) 142 3.7 (3.1-4.4) 112 3.5 (2.9-4.3) 74 2.5 (1.9-3.1) 0.65 (0.54-0.78) 0.62 (0.50-0.75) 0.43 (0.34-0.55) Apocrine-eccrine carcinomas 731 2.8 (2.6-3.1) 82 2.0 (1.5-2.5) 78 2.4 (1.9-3.0) 35 1.1 (0.8-1.6) 0.70 (0.54-0.89) 0.85 (0.66-1.08) 0.40 (0.27-0.56) Adenoid cystic carcinoma 59 0.2 (0.2-0.3) 6 NR 6 NR 5 NR NR NR NR Hidradenocarcinoma 114 0.4 (0.4-0.5) 19 0.5 (0.3-0.8) 18 0.5 (0.3-0.8) 3 NR 1.08 (0.59-1.80) 1.18 (0.67-1.96) NR Microcystic adnexal 202 0.8 (0.7-0.9) 16 0.4 (0.2-0.6) 5 NR 5 NR 0.46 (0.24-0.80) NR NR carcinoma Porocarcinoma 103 0.4 (0.3-0.5) 8 NR 10 0.3 (0.2-0.6) 5 NR NR 0.89 (0.40-1.70) NR Eccrine carcinoma 111 0.4 (0.4-0.5) 11 0.3 (0.1-0.5) 11 0.3 (0.2-0.6) 6 NR 0.68 (0.31-1.28) 0.78 (0.37-1.45) NR Mucinous carcinoma 55 0.2 (0.2-0.3) 5 NR 14 0.5 (0.3-0.8) 6 NR NR 2.20 (1.11-3.99) NR Otherd 87 0.3 (0.3-0.4) 17 0.4 (0.2-0.7) 14 0.4 (0.2-0.7) 5 NR 1.18 (0.64-2.03) 1.15 (0.59-2.06) NR Sebaceous carcinoma 529 2.0 (1.8-2.2) 45 1.3 (0.9-1.7) 17 0.6 (0.3-0.9) 38 1.3 (0.9-1.8) 0.63 (0.45-0.86) 0.28 (0.16-0.44) 0.64 (0.44-0.89) Skin appendage 213 0.8 (0.7-0.9) 15 0.4 (0.2-0.7) 17 0.5 (0.3-0.9) 1 NR 0.52 (0.27-0.90) 0.65 (0.37-1.08) NR carcinoma, NOS

Abbreviations: A/PI, Asian/Pacific Islander; CI, confidence interval; HW, Hispanic white; IRR, incidence rate ratio; NHW, non-Hispanic white; NOS, not otherwise specified; NR, not reported (Ͻ10 cases); SEER, Surveillance, Epidemiology, and End Results. a Excludes Alaska registry and American Indian, Alaska Native, and unknown/other race. b Rates are per 1 million person-years and age-adjusted to the 2000 US standard population (19 age groups20). c Hispanic cases are not mutually exclusive from whites, blacks, and A/PIs. Incidence data for Hispanics are based on North American Association of Central Cancer Registries Hispanic Identification Algorithm (NHIA) and exclude cases from Kentucky. d Other includes apocrine carcinoma, spiradenocarcinoma, digital papillary carcinoma, and malignant mixed tumor.

arial method in SEER*Stat 6.51. Life tables are required to cal- 4.5], respectively; with a male to female incidence rate ra- culate relative SR, and they are not yet available for Hispanic and tio [M:F IRR] of 1.51, PϽ.001) (Table 1). Similarly, men Asian/Pacific Islanders. Therefore, only blacks and whites were had a statistically significant higher IR for most subtypes included in the survival analyses. Relative survival is defined as of apocrine-eccrine carcinomas than women (2.9 [95% CI, the ratio of the proportion of observed survivors in a cohort of 2.7-3.2] vs 2.4 [95% CI, 2.2-2.6], respectively; M:F IRR, patients to the proportion of expected survivors in a compa- rable cohort of the general population (http://srab.cancer.gov 1.24; P=.002) (Table 1) with few exceptions. The M:F IRRs /survival/measures.html), thus representing survival in the ab- ranged between 0.63 and 2.34 for the various apocrine- sence of other causes of death. Only cases with CAC as the first eccrine carcinomas subtypes and were significantly raised primary cancer were included in the survival analysis. The pe- for porocarcinoma (M:F IRR, 2.34; PϽ.001) and hidrad- riod of survival was from the date of diagnosis to the date of last enocarcinoma (M:F IRR, 1.53; P=.01). In contrast to other contact, death, or December 31, 2005. apocrine-eccrine carcinomas subtypes, we found that The following SEER staging system was localized for tu- women had higher IRs for microcystic adnexal carci- mors regardless of size that were confined to the organ of ori- noma and mucinous adenocarcinoma compared with men gin, regional for those that metastasized to the regional lymph (M:F IRR, 0.93 and 0.63, respectively), although the dif- nodes or extended directly from the organ of origin, and dis- ferences were not significant. Men had a significantly higher tant for carcinoma that metastasized to other parts of the body. IR of sebaceous carcinoma than women (2.4 [95% CI, 2.1- 2.6] vs 1.3 [95% CI, 1.2-1.5], respectively). RESULTS

The number of cases, percentage distribution, and IR of RACE CACs are given according to histologic type in Table 1. In total, 1801 cases (IR, 5.1 [95% CI, 4.8-5.3] per 1 million Age-adjusted IRs for CACs overall were highest among person-years) of CACs were diagnosed among residents of non-Hispanic whites (NHWs) (5.7 [95% CI, 5.4-6.0]), fol- the SEER 16 registries during 2001 through 2005. The most lowed by significantly lower rates among Hispanic common histologic category was apocrine-eccrine carci- whites (HWs) (3.7 [95% CI, 3.1-4.4]; IRR, 0.65), blacks nomas (51% of cases; IR, 2.6 [95% CI, 2.4-2.8]), followed (3.5 [95% CI, 2.9-4.3]; IRR 0.62), and Asian/Pacific by sebaceous carcinoma (35% of cases; IR, 1.8 [95% CI, Islanders (A/PIs) (2.5 [95% CI, 1.9-3.1]; IRR, 0.43) (all Ͻ 1.6-1.9]). Of the apocrine-eccrine carcinomas, microcys- P .001) (Table 2). Similarly, age-adjusted IRs of apo- tic adnexal carcinoma was the most common subtype, ac- crine-eccrine carcinomas overall were highest among counting for 25% of cases (IR, 0.6), followed by hidrad- NHWs (2.8 [95% CI, 2.6-3.1]), followed by blacks (2.4 enocarcinoma (17%; IR, 0.4). Less common carcinomas [95% CI, 1.9-3.0]), HWs (2.0 [95% CI, 1.5-2.5]), and A/PIs included adenoid cystic carcinoma (8%) and spiradeno- (1.1 [95% CI, 0.8-1.6]). Compared with NHWs, HWs (IRR, Ͻ carcinoma (3%). 0.70; P=.003), and A/PIs (IRR, 0.40; P .001) had statistically significant lower IRs of apocrine-eccrine carcino- SEX mas overall. However, blacks had a similar IR to NHWs (IRR, 0.85; P=.21). Although analysis by race/ethnicity was Overall, men had a statistically significant higher IR of CAC hampered for many of the subtypes because of the low than women (6.3 [95% CI, 5.9-6.7] vs 4.2 [95% CI, 3.9- number of cases, we identified some important findings

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A B C Total Porocarcinoma Microcystic adnexal carcinoma 100 Apocrine-eccrine carcinomas 100 Eccrine carcinoma 100 Hidradenocarcinoma Sebaceous carcinoma Mucinous carcinoma Other apocrine-eccrine carcinomas Skin appendage carcinoma, NOS Adenoid cystic carcinoma

10 10 10

1 1 1 IR per 1 Million Person-years

0.1 0.1 0.1 20 40 60 80 100 20 40 60 80 100 20 40 60 80 100 Age at Diagnosis, y Age at Diagnosis, y Age at Diagnosis, y

Figure 1. Age-specific cutaneous appendageal carcinoma incidence rates (IRs), in Surveillance, Epidemiology, and End Results 16 from 2001 through 2005.18 A, All appendageal carcinomas (total), apocrine-eccrine tumors, sebaceous carcinoma, and skin appendage carcinoma, not otherwise specified (NOS); B, apocrine-eccrine carcinoma subtypes including porocarcinoma, eccrine carcinoma, mucinous carcinoma, and adenoid-cystic carcinoma; C, apocrine-eccrine carcinoma subtypes including microcystic adnexal carcinoma, hidradenocarcinoma, and other apocrine-eccrine carcinoma (including apocrine carcinoma, spiradenocarcinoma, digital papillary carcinoma, and malignant mixed tumor).

among apocrine-eccrine carcinomas (Table 2). Hispanic after age 65 years for adenoid cystic carcinoma and peaked whites had a lower IR of microcystic adnexal carcinoma around age 75 years for mucinous adenocarcinoma. (0.4) than NHWs (0.8) (IRR, 0.46; P=.003). Blacks had a The median ages of diagnosis are given for the various higher IR of mucinous adenocarcinoma (0.5) than non- CACs in Table 1. Cutaneous appendageal carcinomas have Hispanic whites (0.2) (IRR, 2.20; P=.03). a median age of occurrence in the late seventh or early eighth The sebaceous carcinoma IR was highest among NHWs decade of life, with the exception of digital papillary car- (2.0 [95% CI, 1.8-2.2]), followed by HWs (1.3 [95% CI, cinoma (age 48.5 years), malignant mixed tumor (age 57 0.9-1.7]), A/PIs (1.3 [95% CI, 0.9-1.8]), and blacks (0.6 years), and adenoid cystic carcinoma (age 61 years). [95% CI, 0.3-0.9]) (Table 2). Compared with NHWs, HWs (IRR, 0.63; P=.003), blacks (IRR, 0.28; PϽ.001), and TEMPORAL TRENDS A/PIs (IRR, 0.64; PϽ.001) had statistically significantly lower IRs of sebaceous carcinoma. During 1978 through 2005 in the original 9 SEER areas, 2228 cases of CACs were diagnosed. From 1978-1982 to AGE-SPECIFIC INCIDENCE 2002-2005, the CAC IRs increased 150%, from 2.0 (95% The CAC IRs increased exponentially with age, with peak CI, 1.74-2.36) to 5.0 (95% CI, 4.63-5.49) (Figure 2). Simi- frequencies in the eighth decade of life (Figure 1A). In- larly, there was a 170% rise for apocrine-eccrine carci- cidence rates of CAC overall increased 100-fold from those noma from 1.0 [95% CI, 0.81-1.25] to 2.7 [95% CI, 2.36- aged 20 to 29 years (0.37) to those 80 years or older (37.3). 2.98]) and a 217% increase for sebaceous carcinoma (0.6 This pattern was generally apparent also for apocrine- [95% CI, 0.48-0.83] to 1.9 [95% CI, 1.63-2.17]). The IR eccrine carcinoma overall and sebaceous carcinoma. There increased for all carcinoma subtypes analyzed except for were no cases of sebaceous carcinoma diagnosed at an age adenoid cystic carcinoma, hidradenocarcinoma, and skin younger than 30 years, and age-specific rates subse- appendage carcinoma, not otherwise specified (NOS) (data quently increased exponentially. not shown). The IR of skin appendage carcinoma, NOS The CAC rates were similar among men and women declined notably after 1995. Rates of sebaceous carci- younger than 50 years but were greatly increased among noma increased exponentially over the entire period. The men compared with women at older ages (data not shown). IRs of CACs overall rose for all stages of disease (local- The M:F IRR for CACs overall, stratified by age group, ized and regional/distant) (data not shown). ranged from 0.91 (age 40-49 years) to 1.82 (age Ն80 years) (data not shown). ANATOMIC LOCATION Apocrine-eccrine subtype IRs all rose rapidly with age (Figure 1B and C). The most rapid and consistent increases Cutaneous appendageal carcinomas overall and seba- were for porocarcinoma and eccrine carcinoma. Incidence ceous carcinomas occurred disproportionately on the face, rates increased rapidly with age but were relatively stable scalp, and neck (Ͼ63% of cases each) (Table 3). Less

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 common sites for CACs overall were the upper and lower quency by subtype. Mucinous carcinoma, microcystic ad- extremities (19%), trunk (17%), and multisite/NOS (1%). nexal carcinoma, and adenoid cystic carcinoma oc- Similarly, apocrine-eccrine carcinomas overall occurred most commonly on the face (69%, 68%, and 43%, curred most commonly on the face and scalp and neck respectively) and digital papillary carcinoma, malignant (55%), though there are variations in site-specific fre- mixed tumor, and porocarcinoma occurred most frequently on the extremities (92%, 59%, and 48%, respectively), while apocrine carcinoma and spiradenocarcinoma occurred most frequently on the trunk (41% and 6 31%, respectively) (Table 3).

SURVIVAL

3 The 5-year relative SR for patients with CACs and apocrine-eccrine carcinomas overall was excellent (96%- 97%) (Table 4) and mostly unchanged when stratified by sex or race. The 5-year relative SRs for apocrine- eccrine carcinoma subtypes were higher than 90%, ex- 1 cept for malignant mixed tumor (84%). There was a lower SR for men with apocrine carcinoma (77% [male] vs 97% [female]) and blacks with sebaceous carcinoma (85% [blacks] vs 96% [whites], respectively). Five-year relative SRs for CACs overall were much higher for cancers

IR per 1 Million Person-years diagnosed with localized (99%) or regional (93%) involvement than those with distant involvement (43%).

COMMENT Total Apocrine-eccrine carcinomas Sebaceous carcinoma To our knowledge, this is the first and largest popula- Skin appendage carcinoma, NOS tion-based study and assessment of racial/ethnic pat- 0.1 terns in CACs overall, based on cases diagnosed among 1980 1990 2000 2010 residents of SEER registries in the US population. Pre- Year of Diagnosis vious reports have been case reports or hospital se- ries9,10,24 with a limited number of cases, except for a few Figure 2. Age-adjusted cutaneous appendageal carcinoma incidence rates in population-based studies7,15 restricted to 1 histologic Surveillance, Epidemiology, and End Results 9 from 1978-1982 to subtype. 2002-200523 by year of diagnosis for all appendageal carcinomas (total), apocrine-eccrine tumors, sebaceous carcinoma, and skin appendage Between 1978-1982 and 2001-2005, age-adjusted IRs carcinoma, not otherwise specified (NOS). increased 150% for CACs overall and 217% for seba-

Table 3. Cutaneous Appendageal Carcinomas Diagnosed During 2001 Through 2005 in the SEER 16 Program Registries18 by Histologic Type: Cases and Percentage Distribution by Anatomic Locationa

Cases, No. (%)

Histologic Type Face Scalp and Neck Trunk Extremitiesb Upper Limb Lower Limb Multisite/NOS Total 875 (48.6) 252 (14.0) 313 (17.4) 342 (19.0) 199 (11.0) 143 (7.9) 19 (1.1) Apocrine-eccrine tumorsc 378 (40.8) 131 (14.1) 165 (17.8) 239 (25.8) 129 (13.9) 110 (11.9) 13 (1.4) Adenoid cystic carcinoma 33 (43.4) 17 (22.4) 16 (21.1) 10 (13.2) 5 (6.6) 5 (6.6) 0 Hidradenocarcinoma 33 (15.7) 25 (11.9) 38 (18.1) 56 (26.7) 27 (12.9) 29 (13.8) 2 (1.0) Microcystic adnexal carcinoma 155 (68.0) 24 (10.5) 19 (8.3) 28 (12.3) 18 (7.9) 10 (4.4) 2 (0.9) Porocarcinoma 32 (25.4) 11 (8.7) 23 (18.3) 60 (47.6) 20 (15.9) 40 (31.7) 0 Eccrine carcinoma 41 (29.5) 27 (19.4) 30 (21.6) 37 (26.6) 24 (17.3) 13 (9.4) 4 (2.9) Mucinous carcinoma 55 (68.8) 14 (17.5) 7 (8.8) 4 (5.0) 3 (3.8) 1 (1.3) 0 Other apocrine-eccrine tumors 29 (23.6) 13 (10.6) 32 (26.0) 44 (35.8) 32 (26.0) 12 (9.8) 5 (4.1) Apocrine carcinoma 18 (32.1) 9 (16.1) 23 (41.1) 4 (7.1) 3 (5.4) 1 (1.8) 2 (3.6) Spiradenocarcinoma 6 (23.1) 3 (11.5) 8 (30.8) 8 (30.8) 5 (19.2) 3 (11.5) 1 (3.8) Digital papillary carcinoma 1 (4.2) 0 0 22 (91.7) 19 (79.2) 3 (12.5) 1 (4.2) Malignant mixed tumor 4 (23.5) 1 (5.9) 1 (5.9) 10 (58.8) 5 (29.4) 5 (29.4) 1 (5.9) Sebaceous carcinoma 395 (62.8) 76 (12.1) 107 (17.0) 48 (7.6) 32 (5.1) 16 (2.5) 3 (0.5) Skin appendage carcinoma, NOS 102 (41.5) 45 (18.3) 41 (16.7) 55 (22.4) 38 (15.4) 17 (6.9) 3 (1.2)

Abbreviations: NOS, not otherwise specified; SEER, Surveillance, Epidemiology, and End Results. a Excludes Alaska registry and American Indian, Alaska Native, and unknown/other race. b Extremities include both upper limb and lower limb combined. c Includes tumor types below and subcategory “other apocrine-eccrine tumors.”

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 4. Five-Year Relative Survival Rates (RSRs)a Among Patients Diagnosed as Having Cutaneous Appendageal Carcinomas During 1992 Through 2004 in the SEER Program Registries18 by Histologic Type, Sex, and Raceb

Sex Race Staged

Overall M F White Black Localized Regional Distant

RSR, RSR, RSR, RSR, RSR, RSR, RSR, RSR, Histologic Type No. % No. % No. % No. % No. % No. % No. % No. % Total 1984 96.5 1024 95.9 960 97.0 1849 96.6 135 95.6 1445 99.2 288 92.8 32 43.4 Apocrine-eccrine tumorsc 844 97.2 422 93.6 422 99.5 759 96.8 85 96.9 596 99.2 136 94.3 19 50.8 Adenoid cystic carcinoma 106 98.6 46 98.1 60 97.7 97 98.4 9 100 62 98.6 21 100 1 NR Hidradenocarcinoma 351 92.8 209 92.1 142 92.4 320 92.0 31 96.9 250 96.4 52 83.8 7 NR Microcystic adnexal carcinoma 155 99.5 62 96.7 93 99.0 151 99.5 4 NR 120 99.8 22 93.9 2 NR Mucinous carcinoma 91 100 33 84.5 58 100 74 100 17 97.2 70 100 11 100 1 NR Other apocrine-eccrine tumors 141 93.8 72 89.0 69 95.9 117 95.5 24 84.9 94 95.6 30 90.7 8 NR Apocrine carcinoma 81 91.7 37 77.0 44 96.7 64 92.2 17 88.9 47 95.5 22 85.5 6 NR Spiradenocarcinoma 21 96.7 12 98.2 9 NR 20 96.7 1 NR 18 93.9 1 NR 0 NR Digital papillary carcinoma 18 100 15 100 3 NR 16 100 2 NR 13 100 3 NR 1 NR Malignant mixed tumor 21 83.5 8 NR 13 79.4 17 88.9 4 NR 16 84.3 4 NR 1 NR Sebaceous carcinoma 687 95.8 374 94.9 313 94.3 663 96.2 24 84.5 528 98.4 78 85.0 6 NR Skin appendage carcinoma, NOS 453 94.8 228 96.4 225 91.9 427 94.5 26 95.3 321 96.8 74 95.4 7 NR

Abbreviations: NOS, not otherwise specified; NR, not reported (Ͻ10 cases); SEER, Surveillance, Epidemiology, and End Results; SR, survival rate. a The period of survival was from the date of diagnosis to the date of last contact, death, or December 31, 2005. b Excludes Alaska registry and American Indian, Alaska Native, and unknown/other race. The rest of California (excluding San Francisco/San Jose-Monterey/Los Angeles), Kentucky, Louisiana, New Jersey contribute cases for diagnosis years 2000 through 2004. The remaining 12 SEER areas contribute cases for the entire period of 1992 through 2004. c Includes tumor types below and subcategory “other apocrine-eccrine tumors.” Porocarcinoma and eccrine carcinoma are not included in survival analyses because of their recent International Classification of Diseases coding. d A total of 219 tumors were unstaged.

ceous carcinoma. It is noteworthy that the decreased IR Epidemiological studies have demonstrated that in- of skin appendage carcinomas, NOS after 1995 might have dividual exposure to UV radiation is related to the risk contributed to the rises in apocrine-eccrine carcinoma of skin cancer.26 UV radiation–type mutations in p53 have and sebaceous carcinoma IRs during that same period but been reported in spiradenocarcinoma and hidradenocar- cannot account for all the increases. The classification cinoma.27 Microcystic adnexal carcinoma was reported of CACs is challenging owing to the complex, overlap- to occur more often on the left than the right side of the ping, or poor differentiation of these neoplasms. How- face, and the left side is expected to receive more UV ra- ever, recent molecular techniques are advancing our un- diation through the driver’s side window.28 Ionizing ra- derstanding of these tumors. Analysis by tumor stage to diation exposure may explain in part the observed trend assess the potential effect of improved detection on tem- because case series of cutaneous microcystic adnexal car- poral trends in incidence showed that both localized and cinoma and malignant clear-cell acrospiroma (hidrad- regional/distant stages had significantly increased an- enocarcinoma) have been reported at previously irradi- nual percentage changes over time (1978-2005). The in- ated sites,29,30 which could be due to direct DNA damage crease in IR for CACs overall for all stages of disease sup- and/or local immunosuppression. Individuals treated with ports the hypothesis that there is a true increase in ionizing radiation as children or adolescents may be par- incidence of CACs, not just improved detection. Age- ticularly at high risk. From the early 1920s to the late specific IRs for CACs overall, sebaceous carcinomas, and 1950s, ionizing radiation was commonly used to treat acne most apocrine-eccrine carcinomas increased exponen- or other inflammatory and benign conditions of the head tially with age. This finding is consistent with reports that and neck.31 This is consistent with the anatomic loca- these carcinomas occur predominantly in middle-aged tion and predilection for elderly persons that we ob- or older individuals.1,25 Our study shows that elderly per- served. Furthermore, from 1980 to 2006, the number of sons bear a disproportionate burden of CACs. The ex- annual computed tomographic scans performed in- planation for the rising IRs is unknown, but UV radia- creased from approximately 3 million to 67 million in tion may be a contributing factor. Cutaneous appendageal the United States.32,33 carcinomas share some of the following similarities with Another possible explanation may be the increasing nonmelanoma skin cancer: (1) rates are higher among population of immunosuppressed individuals due to in- men than women, (2) the rates for exposed body sites fection (ie, human immunodeficiency virus),34,35 immu- are higher than those for nonexposed sites, (3) rates are nosuppressant drugs for organ transplant,24 and/or rheu- lower among those with more skin pigmentation, and matologic or other inflammatory diseases. Cutaneous (4) the temporal trends show that IRs are increasing. The appendageal carcinomas have been reported more fre- observed ethnic differences showing significantly higher quently in organ transplant recipients than immune com- IRs of CACS and head and neck anatomic predilection petent individuals. Organ transplant recipients who are im- among NHWs compared with other racial/ethnic groups munosuppressed have a greatly increased risk of cutaneous are consistent with the hypothesis that UV radiation may appendageal tumors compared with apparently immuno- be a risk factor for CACs. competent individuals. In addition, their tumors are more

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 likely to be malignant and of sebaceous origin.36 The role IRs and SRs. The strengths of this study were the large of environmental exposures including polychlorinated bi- sample size of rare CACs and unbiased ascertainment and phenyls in the development of CACs need to be explored. assessment of cases. However, even though we had a large To our knowledge, this study is the first comprehensive sample size, in some instances it was not large enough investigation of apocrine-eccrine carcinoma IR according to allow for sufficient power to calculate stable rates by to histologic subtypes. In our study, apocrine-eccrine car- stratification (especially by race). Other limitations in- cinomas were the most common carcinoma category, ac- cluded the lack of centralized pathologic review of cases, countingfor51%ofcases(IR,2.6per1millionperson-years). error introduced through missing or incomplete data in In contrast to previous studies, we found a male predomi- the registry, and potential underestimation of IRs owing nance for CACs overall and for most of the major catego- to reporting delays and incomplete inclusion of all pa- ries and subtypes except for microcystic adnexal carcino- tients diagnosed at dermatologist’s offices into SEER. How- ma and mucinous carcinoma. Previous case series studies ever, pathologic specimens sent from a dermatologist’s using proportion of cases reported a female predominance office to a hospital for diagnosis would be identified by for adenoid cystic carcinoma, hidradenocarcinoma, and mi- SEER staff and included if a resident of the SEER catch- crocystic adnexal carcinoma1,10 and no sex predilection for ment area. Recently, SEER has mounted considerable ef- spiradenocarcinoma, apocrine carcinoma, and porocarci- fort to identify those cases diagnosed at a dermatolo- noma.1,9 A possible explanation for the discrepancy is that gist’s office not ascertained otherwise. previous studies were small clinical or hospital-based case In conclusion, this study has shown variation in in- series and did not report age-adjusted IRs. Because most pa- cidence patterns by race, sex, age, and histologic type, tients with CACs described in previous clinical series1,9,10 had supporting the notion that CACs represent distinct dis- advancedageatdiagnosis,thefemalepredominancereported ease entities. Since 1978, there was a 150% increase in may be due to women living longer than men. CAC IR. Further increases in CAC incidence over time Our findings on the anatomic distribution contrast with should prompt new strategies for cancer screening and some of the scant reports in the literature.1,10,11,15,37-39 Apo- early intervention of this cancer. Our study showed pre- crine-eccrine carcinoma subtypes occurred with unique site viously unrecognized epidemiological features that may distributions. Adenoid cystic carcinoma occurred most com- ultimately be characteristic findings of the various sub- monly on the face (43%), though it has been previously types. An NHW, male, and head and neck predomi- reported most frequently on the scalp (35%) or the trunk nance was evident for most CAC subtypes. We also found (24%).1,10 Porocarcinoma occurred more on the head and that male predominance of CAC increased with age. Fur- neck (33%) and less on the lower extremities (32%) com- ther investigations using large populations and molecu- pared with previous reports (20% and 60%, respectively).1 lar tools are warranted to elucidate the etiology of indi- Hidradenocarcinoma occurred equally on both the ex- vidual types of CAC. tremities and head and neck (27%), in contrast to other reports of a predilection for the head and neck.1,11 Apo- Accepted for Publication: October 27, 2009. crine carcinoma occurred commonly on the head and neck Correspondence: Jorge R. Toro, MD, Genetic Epidemi- in contrast to a previous reports showing predilection for ology Branch, Division of Cancer Epidemiology and Ge- the axillae.1 Microcystic adnexal carcinoma and muci- netics, National Cancer Institute, 6120 Executive Blvd, nous carcinoma occurred most commonly on the face simi- Executive Plaza South, Room 7012, Rockville, MD 20892- lar to previous reports.1,15 The anatomic distribution of 7231 ([email protected]). digital papillary carcinoma, porocarcinoma, and spirad- Author Contributions: Dr Toro had full access to all the enocarcinoma are similar to past reports.1,13,37,40 data in the study and takes responsibility for the integ- Our survival analysis was based on relative SRs, which rity of the data and the accuracy of the data analysis. Mr were adjusted for mortality in the general population and Blake and Dr Bradford contributed equally to this inves- represents survival in the absence of other causes of death. tigation. Study concept and design: Toro. Acquisition of data: Previous case series of CACs have offered crude sur- Bradford. Analysis and interpretation of data: Blake, Brad- vival proportions or disease-free survival intervals17,41 ford, Devesa, and Toro. Drafting of the manuscript: Blake rather than 5-year relative survival. These differences in and Toro. Critical revision of the manuscript for impor- methodology may explain the differences in survival be- tant intellectual content: Bradford and Devesa. Statistical tween our study and previous reports. Furthermore, in analysis: Bradford. Obtained funding: Toro. Administra- our study most CACs were diagnosed at a localized stage, tive, technical, and material support: Toro. Study supervi- which may explain in part the overall high SRs. Impor- sion: Devesa and Toro. tantly, CACs may have an indolent nature and long tumor- Financial Disclosure: None reported. free intervals.10,40 We found excellent survival among pa- Funding/Support: This study was supported by the In- tients with sebaceous carcinoma, which is in agreement tramural Research Program of the National Institutes of with a previous study using SEER data from 1973 through Health, National Cancer Institute, Division of Cancer Epi- 2004.8 The slightly better SRs in our study (96%) may demiology and Genetics, Genetic Epidemiology Branch. be because our analysis was restricted to data from 1992 Role of the Sponsor: The sponsor had no role in the de- through 2004. Other possibilities include changes in di- sign and conduct of the study; in the collection, analy- agnostic practice and improved treatment over time. sis, and interpretation of data; or in the preparation, re- We conducted a population-based study, which avoids view, or approval of the manuscript. the biases associated with hospital and clinical series and Previous Presentation: This study was presented at the 10th provided us with enough statistical power to calculate International Congress of Dermatology; May 20-24, 2009;

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