Malignant adnexal tumors of the skin: a single institution experience

Malignant adnexal tumors of the skin: a single institution experience Background: Malignant adnexal tumors of the skin (MATS) are rare. We aimed to measure the survival of patients with MATS and identify predictors of improved survival. Methods: A retrospective review of MATS treated at our institution from 1990 to 2012. Results: There were 50 patients within the time period. Median age was 59.5 years (range 22–95); primary site was the head and neck (52%); most common histologic subtypes were skin appendage carcinoma (20%) and eccrine adenocarcinoma (20%); and the vast majority were T1 (44%). Most patients (98%) underwent surgical treatment. Chemotherapy and radiation were administered to 8 and 14% of patients, respectively. Recurrence rate was 12%. Median OS was 158 months (95% CI, 52–255). OS and recurrence-free survival at 5 years were 62.4 and 47.4% and at 10 years 56.7 and 41.5%, respectively. Five-year and 10-year disease-specific survival (DSS) was 62.9%. Age > 60 years was an unfavorable predictor of OS (HR 12.9, P < .0008) and recurrence-free survival (RFS) (HR 12.53, P < .0003). Nodal metastasis was a negative predictor of RFS (HR 2.37, P < 0.04) and DSS (HR 7.2, P < 0.03) while treatment with chemotherapy was predictive of poor DSS (HR 14.21, P <0.03). Conclusions: Younger patients had better OS and RFS. Absence of nodal metastasis translated to better RFS and DSS. Lymph node basin staging is worth considering in the workup and treatment. Keywords: Malignant, Adnexal, Tumors, Skin, Survival, Treatment Background statistically significantly higher than women (6.3 vs 4.2, Malignant adnexal tumors of the skin (MATS) are a hetero- respectively; male to female incidence rate ratio is 1.51; geneous group of rare tumors without consensus on man- P < .001). The incidence rates for these tumors have in- agement guidelines. There are different histologic entities creased by as much as 150% in the last three decades based on varying differentiation from eccrine, apocrine, se- making it imperative that we expand our understanding baceous, sweat duct, or ceruminous glands within the skin of these tumors to make informed decisions regarding or follicular cells [1]. They vary in behavior and malignant prognosis and treatment [4]. With this in mind, we potential and pose a diagnostic challenge for pathologists sought to define our experience in MATS. and surgeons [2]. Paucity of scientific information on these tumors is reflected by the fact that categorization under the Methods WHO classification of skin carcinomas was performed only A retrospective review of all MATS treated at the Roswell in 2005 [3]. The AJCC staging for non-melanoma and Park Cancer Institute between January 1, 1990, and August non-Merkel cell skin tumors is applied to this group of tu- 31, 2012, was carried out. An institutional review board ap- mors. The age-adjusted incidence rate for MATS is 5.1 per proval was obtained for the study. These patients were one million person-years. The incidence rate among men is identified through the Institute’s tumor registry. Relevant demographic, clinical, staging, pathologic, and outcome * Correspondence: tolutopeo@yahoo.com data were obtained for each patient. Adult patients aged Department of Surgical Oncology, Barbara Ann Karmanos Cancer Institute at 18 years and above with histologic diagnosis of malignant McLaren Flint, 4100 Beecher Road, Flint, MI 48532, USA Full list of author information is available at the end of the article adnexal tumors of the skin were included in the study. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 2 of 7 Patients with concurrent diagnosis of squamous cell carcin- Tumor characteristics oma, basal cell carcinoma, and melanoma were excluded. Over half of the series (56%) involved the head and neck Descriptive characteristics like frequencies were com- region (Table 1). The histology subtypes are outlined in puted for categorical variables like gender, histologic Table 3. Perineural invasion and lymphovascular invasion diagnosis, primary site of disease, and type of surgical were uncommonly observed at 4 and 2%, respectively treatment, while numeric variables were summarized (Table 1). Twenty-nine patients (58%) had undocumented using mean with standard deviation, median, and range. histologic grades, while intermediate and poor grades of We determined overall survival, disease-specific survival, differentiation constituted 16% each. The remaining 10% and recurrence-free survival for our series (Figs. 1, 2 and 3). were well differentiated (Table 1). Overall survival was defined as the time between the date of diagnosis and the date of death or the date of last follow-up Treatment or August 31, 2012. Disease-specific survival was defined as Altogether, 49 patients [98%] underwent surgery-wide local the time between the date of diagnosis and the date of death excision (30%), Moh’s micrographic surgery (22%), and sim- specifically from MATS, while recurrence-free survival was ple excision (46%) (Table 1). One patient with skin append- the time between initial treatment of disease and local, re- age carcinoma involving the eyebrow was treated primarily gional, or systemic recurrence of disease. with chemotherapy (carboplatin and taxol) followed by ra- Overall, recurrence-free, and disease-specific survival diation (70 Gy). Four patients (8%) received chemotherapy. analyses were done using the Kaplan-Meier method. Uni- Three of whom were treated adjuvantly, while one was pri- variate and multivariate analyses were done, using Cox mary systemic chemotherapy. Out of the three which re- proportional hazards regression models, to determine pre- ceived adjuvant chemotherapy, one was treated with dictors of overall survival, recurrence-free survival, and radiotherapy as well. Single-agent regimen was adminis- disease-specific survival. Variables used in the regression tered to two patients using cisplatin and paclitaxel, respect- analyses include age, gender, primary site of disease, histo- ively. The remaining two patients received multiple-agent logic subtype, type of surgical treatment, chemotherapy, regimen. One was treated with carboplatin and paclitaxel, radiation treatment, histologic grade, and TNM stage. while the other received adriamycin, cytoxan, and pacli- taxel. The indications for chemotherapy were nodal metas- Results tasis (2 patients), positive margin and perineural invasion (1 Patient characteristics patient), and aggressive disease with periorbital involvement Fifty patients were identified in this analysis. Fifty-six which would have necessitated extensive resection with or- percent (28) of patients in our series were males, while bital exenteration in an octogenarian. Seven patients had 52% (26) were less than or 60 years old (Table 1). The radiotherapy—twoofwhomalsohad chemotherapy (as in- median and mean ages for the series were 59.5 and dicated above). Out of these seven patients, six received ra- 62.4 years, respectively. diation as adjuvant treatment while one received radiation Fig. 1 Overall survival curve Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 3 of 7 Fig. 2 Disease-specific survival curve as part of definitive chemoradiation. The indications for ra- primary on the face which recurred in another area diation were locally aggressive disease, perineural invasion, of the face. The pattern is such that two thirds of pa- and nodal metastasis. tients with recurrent disease had primary site in the head and neck region while the remaining one third Recurrence had lower extremity as the primary site. The histo- The recurrence rate was 12%—three local recurrences, logic subtypes for patients with recurrent disease in- one regional recurrence, and two distant recurrences. clude adenoid cystic carcinoma (2 patients), skin Two of the local recurrences involved the lower ex- appendage carcinoma (2 patients), eccrine adenocar- tremity, while one occurred in the head and neck re- cinoma (1 patient), and sebaceous adenocarcinoma (1 gion. The distant recurrences were from head and patient). Time to recurrence ranged between 12.9 and neck primaries which metastasized to the groin and 56 months, with the median time to recurrence of brain. The only regional occurrence was from a 20.3 months. Fig. 3 Recurrence-free survival curve Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 4 of 7 Table 1 Demographics and univariate analysis Table 1 Demographics and univariate analysis (Continued) Patient characteristics Number (%) OS DSS RFS Patient characteristics Number (%) OS DSS RFS Age Radiation treatment ≤ 60 years 26 (52) 0.001 0.89 0.02 Yes 7 (14) 0.42 0.06 0.47 > 60 years 24 (48) No 43 (86) Sex Recurrence Male 28 (56) 0.73 0.25 0.19 Yes 6 (12) 0.83 –– Female 22 (44) No 40 (80) Primary site Unknown 4 (8) Head and neck 26 (52) Type of recurrence Trunk 8 (16) 0.96 0.87 0.53 Distant 2 (4) 0.98 –– Upper extremities 8 (16) Local 3 (6) Lower extremities 8 (16) Regional 1 (2) Limited observations in perineural invasion, lymphovascular invasion, and T stage recurrence precluded their inclusion in the univariate analysis for OS, DSS, T1 22 (44) 0.18 0.12 0.04 and RFS T2 9 (18) Survival T3 1 (2) The median overall survival for our series was T4 5 (10) 158 months (95% CI 52, 255 months). Five-year OS was Tx 13 (26) 62.4% (95% CI 43.4, 76.6), while the 10-year OS was N stage 56.7% (95% CI 36.4–72.7). Univariate analysis showed that advanced age (greater than 60 years) was a negative N0 44 (88) 0.15 0.01 0.03 predictor (P = 0.001) of OS (Table 1). Both 5-year and N1 4 (8) 10-year disease-specific survival was 62.9% (95% CI N2 2 (4) 39.3–79.4). Nodal disease (P = 0.03) and treatment with M stage chemotherapy (P = 0.02) were associated with worse M0 30 (60) 0.54 0.19 0.16 disease-specific survival (DSS) on univariate analysis M1 0 (0) (Table 1). The recurrence-free survival rate was 47.4% (95% CI 28.2–64.4) at 5 years and 41.5% (95% CI 22.21– Mx 20 (40) 59.8) at 10 years. Age greater than 60 years (P = 0.02), Histologic grade advanced T stage (P = 0.04), and nodal disease (P = 0.03) G1 5 (10) 0.92 0.85 0.85 were negative predictors of recurrence-free survival G2 8 (16) (RFS) on univariate analysis (Table 1). G3 8 (16) On multivariate analysis, age greater than 60 years Gx 29 (58) (P = 0.0008, HR = 12.9) was an independent negative predictor of overall survival. The presence of nodal Perineural invasion disease (P = 0.03, HR = 7.2) and treatment with chemo- Present 2 (4) –– – therapy (P = 0.03, HR = 14.2) turned out as independent Absent 48 (96) negative predictors of DSS. Similarly, advanced age Lymphovascular invasion (P = 0.0003, HR 12.5) and nodal disease (P =0.04, HR Present 1 (2) –– – 2.4) were independently predictive of higher incidence Absent 49 (98) of recurrence on multivariate analysis (Table 2). Type of surgery Discussion Wide excision 15 (30) 0.47 0.39 0.17 Previous studies have reported median ages ranging Mohs surgery 11 (22) from 68 to 70 years [1, 4, 5]. The mean and median ages Local excision 23 (46) reported for our series were closer to those reported in a Chemotherapy 48-patient series of microcystic adnexal carcinoma/scler- Yes 4 (8) 0.40 0.02 0.13 osing sweat duct carcinoma [6], which constituted 12% of histologic subtypes in our series (Table 3). Advanced No 46 (92) age greater than 60 years was independently predictive of poor overall and recurrence-free survival in our study. Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 5 of 7 Table 2 Multivariate analysis for OS, DSS, and RFS HR (hazard ratio), 95% CI, and P value OS DSS RFS Patient characteristics Age ≤ 60 years 12.90 (2.87–57.95), 0.0008 – 12.53 (3.21–48.95), 0.003 > 60 years Nodal metastasis – 7.22 (0.722–72.186), 0.03 2.37 (0.22–25.05), 0.04 Chemotherapy – 14.21 (1.27, − 158.91), 0.03 – This aligned well with the findings in other series where porocarcinoma, apocrine carcinoma [10], and microcystic poor OS was observed on univariate analysis for patients adnexal carcinoma [11]. The histologic grade of the tu- with age greater than 70 years. Martinez et al. and Avra- mors was not predictive of OS, DSS, and RFS on univari- ham et al. reported OS and DSS advantage with the fe- ate and multivariate analysis in our series. Caution, male gender [1, 5], but gender was not predictive of OS, however, must be exercised as 58% of patients did not DSS, or RFS in our series. However, gender distribution have documented histologic grade. This is a reflection of showed male predominance (56%) in our study, a finding how pathology reporting system for this group of tumors concordant with the Blake’s series [4] but in contrast has evolved over the years, with grade reported for the with other studies [3, 7]. more recent cases. This trend was similarly observed in Over half (52%) of the MATS in our series were located other series, with undocumented histologic grades in the in the head and neck region. This is consistent with most range of 76 to 81% of patients [1, 5]. A study reported sur- series [1, 4, 5]. The remaining anatomic sites (upper ex- vival advantage for well-differentiated tumors on univari- tremities, lower extremities, and trunk) had equal distribu- ate analysis, but this variable was not predictive on tion of 16% each. The vast majority had early T stage multivariate analysis [5]. Another study also demonstrated disease, with 44% being T1. The proportion of unknown survival advantage with better histologic grades, albeit T stage (Tx) in our series was about half of those in two after excluding patients with distant metastasis [1]. We large population-based series which reported Tx in the did not identify any histologic subtype with survival ad- range of 46–56% [1, 4]. Advanced T stage was a negative vantage in our analysis. The existing literature, however, predictor of recurrence-free survival on univariate analysis showed a mixed picture, with some reporting an advan- (P = 0.04), but this trend failed to persist on multivariate tage for microcystic adnexal carcinoma [5], while other analysis. Unlike squamous cell carcinoma of the skin and studies favored sebaceous adenocarcinoma [4, 12]orapo- melanoma [8, 9], there was no association between T stage crine adenocarcinoma [1]. and nodal metastasis. No patient in our series had distant Surgical nodal staging was done for 12% of the patients metastasis on presentation, although as many as 40% were in our series. Histopathologic nodal evaluation varied from documented as unknown M stage. Two distant recur- 11 to 29% in the literature. There were no standardized cri- rences were documented for adenoid cystic carcinoma teria for selecting patients who required nodal sampling. and skin appendage carcinoma, with primaries in the head Sixty-six percent (4 out of 6) of patients who had nodal and neck region. Distant metastases were recorded in the basin evaluation in our series underwent the procedure be- literature for nodular hidradenocarcinoma, eccrine cause of clinically positive lymph nodes. One patient had sentinel lymph node biopsy done based on surgeon’sclin- Table 3 Histologic subtypes ical decision, while the sixth patient had the procedure Histology Number (%) done due to unfavorable histologic criteria (poor differenti- ation and lymphovascular invasion). In a similarly sized Skin appendage carcinoma 10 (20) series of 48 patients, nodal sampling was done for nine pa- Eccrine adenocarcinoma 10 (20) tients (18.8%) who developed local recurrence [13]. Four Sebaceous adenocarcinoma 9 (18) out of these nine patients demonstrated nodal metastasis. Malignant eccrine poroma 6 (12) This group of researchers advocated for nodal sampling in Sclerosing sweat duct adenocarcinoma 6 (12) patients with recurrent disease whopresumablywereprese- Adenoid cystic carcinoma 5 (10) lected by their aggressive biology. On the other hand, Ogata et al., in a series of nine patients with apocrine carcinoma Malignant eccrine spiradenoma 1 (2) who had wide local excision and routine regional lymph Malignant nodular hidradenoma 1 (2) node dissection, showed nodal disease in all but one patient Porocarcinoma 1 (2) [14]. This group called for routine nodal staging, at least for Apocrine adenocarcinoma 1 (2) apocrine carcinoma. Experience from breast cancer and Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 6 of 7 melanoma has shown that nodal metastasis can be present cancer. For our series, 4% received adjuvant chemotherapy in the absence of clinically positive lymph nodes. Since alone, 10% were treated with adjuvant radiation alone, and nodal basin is grossly under evaluated, we do not have ac- 4% received adjuvant chemoradiation. The survival analysis curate information yet on incidence of nodal metastasis showed poor RFS for patients treated with chemotherapy. and its effect on recurrence and survival. It is worthwhile to These patients may have been preselected by the aggressive evaluate MATS population with nodal metastasis with a biology of their tumors. The role of chemotherapy in these view to determine predictors of nodal metastasis and then patients needs further study. Treatment with radiation, while prospectively validate identified predictors. Prospective val- not associated with poor survival outcome, did not translate idation requires a larger cohort of patients which is always to survival advantage either. a challenge when addressing key issues on these rare tu- Six patients (12%) had recurrent disease in this series. mors. Same could be said to apply to histologic criteria like There were three local recurrences, one regional recur- grade, perineural invasion, and angiolymphatic invasion. rence and two distant recurrences. Four histologic These have been shown to be important in prognostication subtypes were represented in this subgroup: sebaceous for melanoma and many gastrointestinal cancers. If vali- adenocarcinoma (1 regional recurrence), eccrine adeno- dated, they should be incorporated into the staging system carcinoma (1 local recurrence), adenoid cystic carcin- which means pathologists would report these features. Due oma (1 local and 1 distant recurrence), and skin to limited observations in these categories, we did not in- appendage carcinoma (1 local and 1 distant recurrence). clude them in our survival analysis. Only 4% of patients in Four of the patients with recurrent disease had their pri- our series were positive for perineural invasion and 2% for mary lesions located on the head and neck region while lymphovascular invasion. We observed most studies on the remaining two were located on the lower extrem- MATS did not address these two important criteria. ities. Recurrence-free survival analysis was done and The role of adjuvant radiation and chemotherapy is not showed median RFS of 56 months. Five-year and well defined for MATS. To address this, we need a combin- 10-year RFS were 47.4% (95% CI 28.2–64.4) and 41.5% ation of large study populationand detailsonregimenof (95% CI 22.21–59.8), respectively. Univariate analysis treatment. Previous studies with much lower number of pa- showed age greater than 60 years, positive nodal status, tients than our series had reported on adjuvant chemoradia- and advanced T stage as predictors of RFS, but only age tion. The large population-based series from SEER database and positive nodal status persisted as independent pre- were limited, as there was no information on chemotherapy dictors of RFS on multivariate analysis. Data on recur- while radiation treatment was documented as a categorical rence pattern is crucial to patient’s education about the variable without detailed information on selection criteria prognosis of these tumors. There is paucity of similar and dose. Unfortunately, for rare and heterogeneous tumors data in the literature. like MATS, this will always be challenging. Current pro- posals on the role of adjuvant radiation support the use of Conclusion postoperative radiotherapy for cases in which sufficient re- So far, there are few large population-based studies available section margins cannot be achieved because of the anatomic on malignant adnexal tumors of the skin (MATS). Most of site of the lesion or with positive resection margins [14, 15]. these were derived from the SEER database [1, 4, 5]. These There are no defined guidelines/protocols for adjuvant studies had the benefits of large study population and chemotherapy in the management of MATS, but there are broader representation of the population at large. They reported cases of recurrent or metastatic diseases treated were, however, not without their shortcomings which in- with chemotherapeutic and targeted agents [16]. Various cluded lack of uniform pathology reporting, absence of de- chemotherapeutic agents like doxorubicin, mitomycin, vin- tailed information about margin status, recurrences, and cristine, 5-fluorouracil, cyclophosphamide, anthracycline, selection criteria for nodal sampling, adjuvant chemother- bleomycin, paclitaxel, cisplatin, and carboplatin were used in apy, and radiation treatment. We reviewed our 50-patient, different combinations for metastatic disease [17, 18]. Re- single-institution series and were able to address some of sults varied from no response to stable disease and partial re- these limitations, albeit with limited numbers. sponse. This trend was noticed in all four patients (8%) who This study shows that younger patients had better OS and received chemotherapy in our series. The histologic subtypes RFS. Absence of nodal metastasis was also noted to translate represented in this subgroup were adenoid cystic carcinoma, to better RFS and DSS. Lymph node basin staging is worth eccrine adenocarcinoma, apocrine adenocarcinoma, and skin considering in the workup and treatment. More importantly, appendage carcinoma. Chemotherapeutic agents utilized strategies that promote early detection and prompt treat- were cisplatin, carboplatin, adriamycin, cytoxan, and pacli- ment should be emphasized in addressing this disease. taxel. Drawing inference from the apocrine-eccrine origin of Abbreviations many of these tumors, some proponents have made a case DSS: Disease-specific survival; MATS: Malignant adnexal tumors of the skin; for treatment with chemotherapy regimen used for breast OS: Overall survival; RFS: Recurrence-free survival Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 7 of 7 Availability of data and materials 14. Ogata D, Kiyohara Y, Yoshikawa S, Kasami M. Treatment strategy for Please contact author for data requests. cutaneous apocrine carcinoma. Int J Clin Oncol. 2014;19(4):712–5. 15. Romeu M, Foletti JM, Chossegros C, Dales JP, Berbis P, Cribier B, Guyot L. Malignant cutaneous adnexal neoplasms of the face and scalp: Authors’ contributions diagnostic and therapeutic update. J Stomatol Oral Maxillofac Surg. TO conceived of the study and participated in its design and coordination 2017;118(2):95–102. and drafted the manuscript. WT participated in the design of the study and 16. Battistella M, Mateus C, Lassau N, Chami L, Boukoucha M, Duvillard P, et al. performed the statistical analysis. JK, JS, VF, and KS participated in the design Sunitinib efficacy in the treatment of metastatic skin adnexal carcinomas: of the study and helped to draft the manuscript. NK conceived of the study report of two patients with hidradenocarcinoma and trichoblastic and participated in its design and coordination and drafted the manuscript. carcinoma. J Eur Acad Dermatol Venereol. 2010;24(2):199–203. All authors read and approved the final manuscript. 17. Piedbois P, Breau JL, Morere JF, Israel L. Sweat gland carcinoma with bone and visceral metastases. Prolonged complete remission lasting 16 months Ethics approval and consent to participate as a result of chemotherapy. Cancer. 1987;60(2):170–2. The Institutional Review Board of the Roswell Park Cancer Institute approved 18. De Iuliis F, Amoroso L, Taglieri L, Vendittozzi S, Blasi L, Salerno G, Lanza R, the study. Scarpa S. Chemotherapy of rare skin adnexal tumors: a review of literature. Anticancer Res. 2014;34(10):5263–8. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Department of Surgical Oncology, Barbara Ann Karmanos Cancer Institute at McLaren Flint, 4100 Beecher Road, Flint, MI 48532, USA. Received: 23 January 2018 Accepted: 21 May 2018 References 1. Martinez SR, Barr KL, Canter RJ. Rare tumors through the looking glass: an examination of malignant cutaneous adnexal tumors. Arch Dermatol. 2011; 147(9):1058–62. 2. Waqas O, Faisal M, Haider I, Amjad A, Jamshed A, Hussain R. Retrospective study of rare cutaneous malignant adnexal tumors of the head and neck in a tertiary care cancer hospital: a case series. J Med Case Rep. 2017;11:67. 3. Leboit P, Burg G, Weedon D, Sarasin A. World health organization classification of tumors: pathology & genetics: skin tumors, vol. 2006. Lyon: IARCPress; 2006. 4. Blake PW, Bradford PT, Devesa SS, Toro JR. Cutaneous appendageal carcinoma incidence and survival patterns in the United States: a population-based study. Arch Dermatol. 2010;146(6):625–32. 5. Avraham JB, Villines D, Maker VK, August C, Maker AV. Survival after resection of cutaneous adnexal carcinomas with eccrine differentiation: risk factors and trends in outcomes. J Surg Oncol. 2013;108(1):57–62. 6. Chiller K, Passaro D, Scheuller M, Singer M, McCalmont T, Grekin RC. Microcystic adnexal carcinoma: forty-eight cases, their treatment, and their outcome. Arch Dermatol. 2000;136(11):1355–9. 7. Barnes J, Garcia C. Primary cutaneous adenoid cystic carcinoma: a case report and review of the literature. Cutis. 2008;81(3):243–6. 8. Roozeboom MH, Lohman BG, Westers-Attema A, Nelemans PJ, Botterweck AA, van Marion AM, et al. Clinical and histological prognostic factors for local recurrence and metastasis of cutaneous squamous cell carcinoma: analysis of a defined population. Acta Derm Venereol. 2013;93(4):417–21. 9. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. New TNM melanoma staging system: linking biology and natural history to clinical outcomes. Semin Surg Oncol. 2003;21(1):43–52. 10. Guerriero S, Ruffolo C, Lombardi AR, Tirone A, Tirone G. Recurrent pleural effusion and pulmonary metastases from a cutaneous apocrine tumour of the axilla. Acta Chir Belg. 2007;107(6):697–9. 11. Gabillot-Carre M, Weill F, Mamelle G, Kolb F, Boitier F, Petrow P, et al. Microcystic adnexal carcinoma: report of seven cases including one with lung metastasis. Dermatology. 2006;212(3):221–8. 12. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. 2009;115(1):158–65. 13. Barnes M, Hestley A, Murray DR, Carlson GW, Parker D, Delman KA. The risk of lymph node involvement in malignant cutaneous adnexal tumors. Am Surg. 2014;80(3):270–4. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Journal of Surgical Oncology Springer Journals

Malignant adnexal tumors of the skin: a single institution experience

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Abstract

Background: Malignant adnexal tumors of the skin (MATS) are rare. We aimed to measure the survival of patients with MATS and identify predictors of improved survival. Methods: A retrospective review of MATS treated at our institution from 1990 to 2012. Results: There were 50 patients within the time period. Median age was 59.5 years (range 22–95); primary site was the head and neck (52%); most common histologic subtypes were skin appendage carcinoma (20%) and eccrine adenocarcinoma (20%); and the vast majority were T1 (44%). Most patients (98%) underwent surgical treatment. Chemotherapy and radiation were administered to 8 and 14% of patients, respectively. Recurrence rate was 12%. Median OS was 158 months (95% CI, 52–255). OS and recurrence-free survival at 5 years were 62.4 and 47.4% and at 10 years 56.7 and 41.5%, respectively. Five-year and 10-year disease-specific survival (DSS) was 62.9%. Age > 60 years was an unfavorable predictor of OS (HR 12.9, P < .0008) and recurrence-free survival (RFS) (HR 12.53, P < .0003). Nodal metastasis was a negative predictor of RFS (HR 2.37, P < 0.04) and DSS (HR 7.2, P < 0.03) while treatment with chemotherapy was predictive of poor DSS (HR 14.21, P <0.03). Conclusions: Younger patients had better OS and RFS. Absence of nodal metastasis translated to better RFS and DSS. Lymph node basin staging is worth considering in the workup and treatment. Keywords: Malignant, Adnexal, Tumors, Skin, Survival, Treatment Background statistically significantly higher than women (6.3 vs 4.2, Malignant adnexal tumors of the skin (MATS) are a hetero- respectively; male to female incidence rate ratio is 1.51; geneous group of rare tumors without consensus on man- P < .001). The incidence rates for these tumors have in- agement guidelines. There are different histologic entities creased by as much as 150% in the last three decades based on varying differentiation from eccrine, apocrine, se- making it imperative that we expand our understanding baceous, sweat duct, or ceruminous glands within the skin of these tumors to make informed decisions regarding or follicular cells [1]. They vary in behavior and malignant prognosis and treatment [4]. With this in mind, we potential and pose a diagnostic challenge for pathologists sought to define our experience in MATS. and surgeons [2]. Paucity of scientific information on these tumors is reflected by the fact that categorization under the Methods WHO classification of skin carcinomas was performed only A retrospective review of all MATS treated at the Roswell in 2005 [3]. The AJCC staging for non-melanoma and Park Cancer Institute between January 1, 1990, and August non-Merkel cell skin tumors is applied to this group of tu- 31, 2012, was carried out. An institutional review board ap- mors. The age-adjusted incidence rate for MATS is 5.1 per proval was obtained for the study. These patients were one million person-years. The incidence rate among men is identified through the Institute’s tumor registry. Relevant demographic, clinical, staging, pathologic, and outcome * Correspondence: tolutopeo@yahoo.com data were obtained for each patient. Adult patients aged Department of Surgical Oncology, Barbara Ann Karmanos Cancer Institute at 18 years and above with histologic diagnosis of malignant McLaren Flint, 4100 Beecher Road, Flint, MI 48532, USA Full list of author information is available at the end of the article adnexal tumors of the skin were included in the study. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 2 of 7 Patients with concurrent diagnosis of squamous cell carcin- Tumor characteristics oma, basal cell carcinoma, and melanoma were excluded. Over half of the series (56%) involved the head and neck Descriptive characteristics like frequencies were com- region (Table 1). The histology subtypes are outlined in puted for categorical variables like gender, histologic Table 3. Perineural invasion and lymphovascular invasion diagnosis, primary site of disease, and type of surgical were uncommonly observed at 4 and 2%, respectively treatment, while numeric variables were summarized (Table 1). Twenty-nine patients (58%) had undocumented using mean with standard deviation, median, and range. histologic grades, while intermediate and poor grades of We determined overall survival, disease-specific survival, differentiation constituted 16% each. The remaining 10% and recurrence-free survival for our series (Figs. 1, 2 and 3). were well differentiated (Table 1). Overall survival was defined as the time between the date of diagnosis and the date of death or the date of last follow-up Treatment or August 31, 2012. Disease-specific survival was defined as Altogether, 49 patients [98%] underwent surgery-wide local the time between the date of diagnosis and the date of death excision (30%), Moh’s micrographic surgery (22%), and sim- specifically from MATS, while recurrence-free survival was ple excision (46%) (Table 1). One patient with skin append- the time between initial treatment of disease and local, re- age carcinoma involving the eyebrow was treated primarily gional, or systemic recurrence of disease. with chemotherapy (carboplatin and taxol) followed by ra- Overall, recurrence-free, and disease-specific survival diation (70 Gy). Four patients (8%) received chemotherapy. analyses were done using the Kaplan-Meier method. Uni- Three of whom were treated adjuvantly, while one was pri- variate and multivariate analyses were done, using Cox mary systemic chemotherapy. Out of the three which re- proportional hazards regression models, to determine pre- ceived adjuvant chemotherapy, one was treated with dictors of overall survival, recurrence-free survival, and radiotherapy as well. Single-agent regimen was adminis- disease-specific survival. Variables used in the regression tered to two patients using cisplatin and paclitaxel, respect- analyses include age, gender, primary site of disease, histo- ively. The remaining two patients received multiple-agent logic subtype, type of surgical treatment, chemotherapy, regimen. One was treated with carboplatin and paclitaxel, radiation treatment, histologic grade, and TNM stage. while the other received adriamycin, cytoxan, and pacli- taxel. The indications for chemotherapy were nodal metas- Results tasis (2 patients), positive margin and perineural invasion (1 Patient characteristics patient), and aggressive disease with periorbital involvement Fifty patients were identified in this analysis. Fifty-six which would have necessitated extensive resection with or- percent (28) of patients in our series were males, while bital exenteration in an octogenarian. Seven patients had 52% (26) were less than or 60 years old (Table 1). The radiotherapy—twoofwhomalsohad chemotherapy (as in- median and mean ages for the series were 59.5 and dicated above). Out of these seven patients, six received ra- 62.4 years, respectively. diation as adjuvant treatment while one received radiation Fig. 1 Overall survival curve Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 3 of 7 Fig. 2 Disease-specific survival curve as part of definitive chemoradiation. The indications for ra- primary on the face which recurred in another area diation were locally aggressive disease, perineural invasion, of the face. The pattern is such that two thirds of pa- and nodal metastasis. tients with recurrent disease had primary site in the head and neck region while the remaining one third Recurrence had lower extremity as the primary site. The histo- The recurrence rate was 12%—three local recurrences, logic subtypes for patients with recurrent disease in- one regional recurrence, and two distant recurrences. clude adenoid cystic carcinoma (2 patients), skin Two of the local recurrences involved the lower ex- appendage carcinoma (2 patients), eccrine adenocar- tremity, while one occurred in the head and neck re- cinoma (1 patient), and sebaceous adenocarcinoma (1 gion. The distant recurrences were from head and patient). Time to recurrence ranged between 12.9 and neck primaries which metastasized to the groin and 56 months, with the median time to recurrence of brain. The only regional occurrence was from a 20.3 months. Fig. 3 Recurrence-free survival curve Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 4 of 7 Table 1 Demographics and univariate analysis Table 1 Demographics and univariate analysis (Continued) Patient characteristics Number (%) OS DSS RFS Patient characteristics Number (%) OS DSS RFS Age Radiation treatment ≤ 60 years 26 (52) 0.001 0.89 0.02 Yes 7 (14) 0.42 0.06 0.47 > 60 years 24 (48) No 43 (86) Sex Recurrence Male 28 (56) 0.73 0.25 0.19 Yes 6 (12) 0.83 –– Female 22 (44) No 40 (80) Primary site Unknown 4 (8) Head and neck 26 (52) Type of recurrence Trunk 8 (16) 0.96 0.87 0.53 Distant 2 (4) 0.98 –– Upper extremities 8 (16) Local 3 (6) Lower extremities 8 (16) Regional 1 (2) Limited observations in perineural invasion, lymphovascular invasion, and T stage recurrence precluded their inclusion in the univariate analysis for OS, DSS, T1 22 (44) 0.18 0.12 0.04 and RFS T2 9 (18) Survival T3 1 (2) The median overall survival for our series was T4 5 (10) 158 months (95% CI 52, 255 months). Five-year OS was Tx 13 (26) 62.4% (95% CI 43.4, 76.6), while the 10-year OS was N stage 56.7% (95% CI 36.4–72.7). Univariate analysis showed that advanced age (greater than 60 years) was a negative N0 44 (88) 0.15 0.01 0.03 predictor (P = 0.001) of OS (Table 1). Both 5-year and N1 4 (8) 10-year disease-specific survival was 62.9% (95% CI N2 2 (4) 39.3–79.4). Nodal disease (P = 0.03) and treatment with M stage chemotherapy (P = 0.02) were associated with worse M0 30 (60) 0.54 0.19 0.16 disease-specific survival (DSS) on univariate analysis M1 0 (0) (Table 1). The recurrence-free survival rate was 47.4% (95% CI 28.2–64.4) at 5 years and 41.5% (95% CI 22.21– Mx 20 (40) 59.8) at 10 years. Age greater than 60 years (P = 0.02), Histologic grade advanced T stage (P = 0.04), and nodal disease (P = 0.03) G1 5 (10) 0.92 0.85 0.85 were negative predictors of recurrence-free survival G2 8 (16) (RFS) on univariate analysis (Table 1). G3 8 (16) On multivariate analysis, age greater than 60 years Gx 29 (58) (P = 0.0008, HR = 12.9) was an independent negative predictor of overall survival. The presence of nodal Perineural invasion disease (P = 0.03, HR = 7.2) and treatment with chemo- Present 2 (4) –– – therapy (P = 0.03, HR = 14.2) turned out as independent Absent 48 (96) negative predictors of DSS. Similarly, advanced age Lymphovascular invasion (P = 0.0003, HR 12.5) and nodal disease (P =0.04, HR Present 1 (2) –– – 2.4) were independently predictive of higher incidence Absent 49 (98) of recurrence on multivariate analysis (Table 2). Type of surgery Discussion Wide excision 15 (30) 0.47 0.39 0.17 Previous studies have reported median ages ranging Mohs surgery 11 (22) from 68 to 70 years [1, 4, 5]. The mean and median ages Local excision 23 (46) reported for our series were closer to those reported in a Chemotherapy 48-patient series of microcystic adnexal carcinoma/scler- Yes 4 (8) 0.40 0.02 0.13 osing sweat duct carcinoma [6], which constituted 12% of histologic subtypes in our series (Table 3). Advanced No 46 (92) age greater than 60 years was independently predictive of poor overall and recurrence-free survival in our study. Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 5 of 7 Table 2 Multivariate analysis for OS, DSS, and RFS HR (hazard ratio), 95% CI, and P value OS DSS RFS Patient characteristics Age ≤ 60 years 12.90 (2.87–57.95), 0.0008 – 12.53 (3.21–48.95), 0.003 > 60 years Nodal metastasis – 7.22 (0.722–72.186), 0.03 2.37 (0.22–25.05), 0.04 Chemotherapy – 14.21 (1.27, − 158.91), 0.03 – This aligned well with the findings in other series where porocarcinoma, apocrine carcinoma [10], and microcystic poor OS was observed on univariate analysis for patients adnexal carcinoma [11]. The histologic grade of the tu- with age greater than 70 years. Martinez et al. and Avra- mors was not predictive of OS, DSS, and RFS on univari- ham et al. reported OS and DSS advantage with the fe- ate and multivariate analysis in our series. Caution, male gender [1, 5], but gender was not predictive of OS, however, must be exercised as 58% of patients did not DSS, or RFS in our series. However, gender distribution have documented histologic grade. This is a reflection of showed male predominance (56%) in our study, a finding how pathology reporting system for this group of tumors concordant with the Blake’s series [4] but in contrast has evolved over the years, with grade reported for the with other studies [3, 7]. more recent cases. This trend was similarly observed in Over half (52%) of the MATS in our series were located other series, with undocumented histologic grades in the in the head and neck region. This is consistent with most range of 76 to 81% of patients [1, 5]. A study reported sur- series [1, 4, 5]. The remaining anatomic sites (upper ex- vival advantage for well-differentiated tumors on univari- tremities, lower extremities, and trunk) had equal distribu- ate analysis, but this variable was not predictive on tion of 16% each. The vast majority had early T stage multivariate analysis [5]. Another study also demonstrated disease, with 44% being T1. The proportion of unknown survival advantage with better histologic grades, albeit T stage (Tx) in our series was about half of those in two after excluding patients with distant metastasis [1]. We large population-based series which reported Tx in the did not identify any histologic subtype with survival ad- range of 46–56% [1, 4]. Advanced T stage was a negative vantage in our analysis. The existing literature, however, predictor of recurrence-free survival on univariate analysis showed a mixed picture, with some reporting an advan- (P = 0.04), but this trend failed to persist on multivariate tage for microcystic adnexal carcinoma [5], while other analysis. Unlike squamous cell carcinoma of the skin and studies favored sebaceous adenocarcinoma [4, 12]orapo- melanoma [8, 9], there was no association between T stage crine adenocarcinoma [1]. and nodal metastasis. No patient in our series had distant Surgical nodal staging was done for 12% of the patients metastasis on presentation, although as many as 40% were in our series. Histopathologic nodal evaluation varied from documented as unknown M stage. Two distant recur- 11 to 29% in the literature. There were no standardized cri- rences were documented for adenoid cystic carcinoma teria for selecting patients who required nodal sampling. and skin appendage carcinoma, with primaries in the head Sixty-six percent (4 out of 6) of patients who had nodal and neck region. Distant metastases were recorded in the basin evaluation in our series underwent the procedure be- literature for nodular hidradenocarcinoma, eccrine cause of clinically positive lymph nodes. One patient had sentinel lymph node biopsy done based on surgeon’sclin- Table 3 Histologic subtypes ical decision, while the sixth patient had the procedure Histology Number (%) done due to unfavorable histologic criteria (poor differenti- ation and lymphovascular invasion). In a similarly sized Skin appendage carcinoma 10 (20) series of 48 patients, nodal sampling was done for nine pa- Eccrine adenocarcinoma 10 (20) tients (18.8%) who developed local recurrence [13]. Four Sebaceous adenocarcinoma 9 (18) out of these nine patients demonstrated nodal metastasis. Malignant eccrine poroma 6 (12) This group of researchers advocated for nodal sampling in Sclerosing sweat duct adenocarcinoma 6 (12) patients with recurrent disease whopresumablywereprese- Adenoid cystic carcinoma 5 (10) lected by their aggressive biology. On the other hand, Ogata et al., in a series of nine patients with apocrine carcinoma Malignant eccrine spiradenoma 1 (2) who had wide local excision and routine regional lymph Malignant nodular hidradenoma 1 (2) node dissection, showed nodal disease in all but one patient Porocarcinoma 1 (2) [14]. This group called for routine nodal staging, at least for Apocrine adenocarcinoma 1 (2) apocrine carcinoma. Experience from breast cancer and Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 6 of 7 melanoma has shown that nodal metastasis can be present cancer. For our series, 4% received adjuvant chemotherapy in the absence of clinically positive lymph nodes. Since alone, 10% were treated with adjuvant radiation alone, and nodal basin is grossly under evaluated, we do not have ac- 4% received adjuvant chemoradiation. The survival analysis curate information yet on incidence of nodal metastasis showed poor RFS for patients treated with chemotherapy. and its effect on recurrence and survival. It is worthwhile to These patients may have been preselected by the aggressive evaluate MATS population with nodal metastasis with a biology of their tumors. The role of chemotherapy in these view to determine predictors of nodal metastasis and then patients needs further study. Treatment with radiation, while prospectively validate identified predictors. Prospective val- not associated with poor survival outcome, did not translate idation requires a larger cohort of patients which is always to survival advantage either. a challenge when addressing key issues on these rare tu- Six patients (12%) had recurrent disease in this series. mors. Same could be said to apply to histologic criteria like There were three local recurrences, one regional recur- grade, perineural invasion, and angiolymphatic invasion. rence and two distant recurrences. Four histologic These have been shown to be important in prognostication subtypes were represented in this subgroup: sebaceous for melanoma and many gastrointestinal cancers. If vali- adenocarcinoma (1 regional recurrence), eccrine adeno- dated, they should be incorporated into the staging system carcinoma (1 local recurrence), adenoid cystic carcin- which means pathologists would report these features. Due oma (1 local and 1 distant recurrence), and skin to limited observations in these categories, we did not in- appendage carcinoma (1 local and 1 distant recurrence). clude them in our survival analysis. Only 4% of patients in Four of the patients with recurrent disease had their pri- our series were positive for perineural invasion and 2% for mary lesions located on the head and neck region while lymphovascular invasion. We observed most studies on the remaining two were located on the lower extrem- MATS did not address these two important criteria. ities. Recurrence-free survival analysis was done and The role of adjuvant radiation and chemotherapy is not showed median RFS of 56 months. Five-year and well defined for MATS. To address this, we need a combin- 10-year RFS were 47.4% (95% CI 28.2–64.4) and 41.5% ation of large study populationand detailsonregimenof (95% CI 22.21–59.8), respectively. Univariate analysis treatment. Previous studies with much lower number of pa- showed age greater than 60 years, positive nodal status, tients than our series had reported on adjuvant chemoradia- and advanced T stage as predictors of RFS, but only age tion. The large population-based series from SEER database and positive nodal status persisted as independent pre- were limited, as there was no information on chemotherapy dictors of RFS on multivariate analysis. Data on recur- while radiation treatment was documented as a categorical rence pattern is crucial to patient’s education about the variable without detailed information on selection criteria prognosis of these tumors. There is paucity of similar and dose. Unfortunately, for rare and heterogeneous tumors data in the literature. like MATS, this will always be challenging. Current pro- posals on the role of adjuvant radiation support the use of Conclusion postoperative radiotherapy for cases in which sufficient re- So far, there are few large population-based studies available section margins cannot be achieved because of the anatomic on malignant adnexal tumors of the skin (MATS). Most of site of the lesion or with positive resection margins [14, 15]. these were derived from the SEER database [1, 4, 5]. These There are no defined guidelines/protocols for adjuvant studies had the benefits of large study population and chemotherapy in the management of MATS, but there are broader representation of the population at large. They reported cases of recurrent or metastatic diseases treated were, however, not without their shortcomings which in- with chemotherapeutic and targeted agents [16]. Various cluded lack of uniform pathology reporting, absence of de- chemotherapeutic agents like doxorubicin, mitomycin, vin- tailed information about margin status, recurrences, and cristine, 5-fluorouracil, cyclophosphamide, anthracycline, selection criteria for nodal sampling, adjuvant chemother- bleomycin, paclitaxel, cisplatin, and carboplatin were used in apy, and radiation treatment. We reviewed our 50-patient, different combinations for metastatic disease [17, 18]. Re- single-institution series and were able to address some of sults varied from no response to stable disease and partial re- these limitations, albeit with limited numbers. sponse. This trend was noticed in all four patients (8%) who This study shows that younger patients had better OS and received chemotherapy in our series. The histologic subtypes RFS. Absence of nodal metastasis was also noted to translate represented in this subgroup were adenoid cystic carcinoma, to better RFS and DSS. Lymph node basin staging is worth eccrine adenocarcinoma, apocrine adenocarcinoma, and skin considering in the workup and treatment. More importantly, appendage carcinoma. Chemotherapeutic agents utilized strategies that promote early detection and prompt treat- were cisplatin, carboplatin, adriamycin, cytoxan, and pacli- ment should be emphasized in addressing this disease. taxel. Drawing inference from the apocrine-eccrine origin of Abbreviations many of these tumors, some proponents have made a case DSS: Disease-specific survival; MATS: Malignant adnexal tumors of the skin; for treatment with chemotherapy regimen used for breast OS: Overall survival; RFS: Recurrence-free survival Oyasiji et al. World Journal of Surgical Oncology (2018) 16:99 Page 7 of 7 Availability of data and materials 14. Ogata D, Kiyohara Y, Yoshikawa S, Kasami M. Treatment strategy for Please contact author for data requests. cutaneous apocrine carcinoma. Int J Clin Oncol. 2014;19(4):712–5. 15. Romeu M, Foletti JM, Chossegros C, Dales JP, Berbis P, Cribier B, Guyot L. Malignant cutaneous adnexal neoplasms of the face and scalp: Authors’ contributions diagnostic and therapeutic update. J Stomatol Oral Maxillofac Surg. TO conceived of the study and participated in its design and coordination 2017;118(2):95–102. and drafted the manuscript. WT participated in the design of the study and 16. Battistella M, Mateus C, Lassau N, Chami L, Boukoucha M, Duvillard P, et al. performed the statistical analysis. JK, JS, VF, and KS participated in the design Sunitinib efficacy in the treatment of metastatic skin adnexal carcinomas: of the study and helped to draft the manuscript. NK conceived of the study report of two patients with hidradenocarcinoma and trichoblastic and participated in its design and coordination and drafted the manuscript. carcinoma. J Eur Acad Dermatol Venereol. 2010;24(2):199–203. All authors read and approved the final manuscript. 17. Piedbois P, Breau JL, Morere JF, Israel L. Sweat gland carcinoma with bone and visceral metastases. Prolonged complete remission lasting 16 months Ethics approval and consent to participate as a result of chemotherapy. Cancer. 1987;60(2):170–2. The Institutional Review Board of the Roswell Park Cancer Institute approved 18. De Iuliis F, Amoroso L, Taglieri L, Vendittozzi S, Blasi L, Salerno G, Lanza R, the study. Scarpa S. Chemotherapy of rare skin adnexal tumors: a review of literature. Anticancer Res. 2014;34(10):5263–8. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Department of Surgical Oncology, Barbara Ann Karmanos Cancer Institute at McLaren Flint, 4100 Beecher Road, Flint, MI 48532, USA. Received: 23 January 2018 Accepted: 21 May 2018 References 1. Martinez SR, Barr KL, Canter RJ. Rare tumors through the looking glass: an examination of malignant cutaneous adnexal tumors. Arch Dermatol. 2011; 147(9):1058–62. 2. Waqas O, Faisal M, Haider I, Amjad A, Jamshed A, Hussain R. Retrospective study of rare cutaneous malignant adnexal tumors of the head and neck in a tertiary care cancer hospital: a case series. J Med Case Rep. 2017;11:67. 3. Leboit P, Burg G, Weedon D, Sarasin A. World health organization classification of tumors: pathology & genetics: skin tumors, vol. 2006. Lyon: IARCPress; 2006. 4. Blake PW, Bradford PT, Devesa SS, Toro JR. Cutaneous appendageal carcinoma incidence and survival patterns in the United States: a population-based study. Arch Dermatol. 2010;146(6):625–32. 5. Avraham JB, Villines D, Maker VK, August C, Maker AV. Survival after resection of cutaneous adnexal carcinomas with eccrine differentiation: risk factors and trends in outcomes. J Surg Oncol. 2013;108(1):57–62. 6. Chiller K, Passaro D, Scheuller M, Singer M, McCalmont T, Grekin RC. Microcystic adnexal carcinoma: forty-eight cases, their treatment, and their outcome. Arch Dermatol. 2000;136(11):1355–9. 7. Barnes J, Garcia C. Primary cutaneous adenoid cystic carcinoma: a case report and review of the literature. Cutis. 2008;81(3):243–6. 8. Roozeboom MH, Lohman BG, Westers-Attema A, Nelemans PJ, Botterweck AA, van Marion AM, et al. Clinical and histological prognostic factors for local recurrence and metastasis of cutaneous squamous cell carcinoma: analysis of a defined population. Acta Derm Venereol. 2013;93(4):417–21. 9. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. New TNM melanoma staging system: linking biology and natural history to clinical outcomes. Semin Surg Oncol. 2003;21(1):43–52. 10. Guerriero S, Ruffolo C, Lombardi AR, Tirone A, Tirone G. Recurrent pleural effusion and pulmonary metastases from a cutaneous apocrine tumour of the axilla. Acta Chir Belg. 2007;107(6):697–9. 11. Gabillot-Carre M, Weill F, Mamelle G, Kolb F, Boitier F, Petrow P, et al. Microcystic adnexal carcinoma: report of seven cases including one with lung metastasis. Dermatology. 2006;212(3):221–8. 12. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. 2009;115(1):158–65. 13. Barnes M, Hestley A, Murray DR, Carlson GW, Parker D, Delman KA. The risk of lymph node involvement in malignant cutaneous adnexal tumors. Am Surg. 2014;80(3):270–4.

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World Journal of Surgical OncologySpringer Journals

Published: May 30, 2018

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