- Email: [email protected]
Malignant eccrine spiradenoma: a meta-analysis of reported cases
The American Journal of Surgery (2011) 201, 695– 699
Reviews
Malignant eccrine spiradenoma: a meta-analysis of reported cases Michael T. Andreoli, B.A.a, Kamal M.F. Itani, M.D.a,b,* a
Boston University, Boston, MA, USA; bDepartment of Surgery, Boston Veterans Affairs Health Care System, 1400 VFW Parkway, 112A, West Roxbury, MA 02132, USA KEYWORDS: Malignant; Eccrine; Spiradenoma; Spiradenocarcinoma; Appendageal; Tumor
Abstract BACKGROUND: Malignant eccrine spiradenoma is an aggressive sweat gland tumor with poorly understood behavior and no currently accepted therapeutic regimen. METHODS: An individual patient data meta-analysis with Kaplan–Meier survival curves was performed on 72 reported cases of malignant eccrine spiradenoma. RESULTS: In 35 patients with no distant metastasis, local resection resulted in 100% disease-free survival. Of 7 patients with lymph node but no distant metastasis treated with surgical resection and lymph node dissection, 6 patients remained disease-free at final follow-up evaluation. For the 24 cases with confirmed distant metastatic disease, patient survival did not significantly differ between local resection and surgery with adjuvant chemoradiotherapy (P ⫽ .8763). CONCLUSIONS: Heightened awareness is recommended among surgeons likely to treat this entity. An aggressive surgical approach is supported in the absence of metastasis. When lymph nodes are not clinically involved, sentinel node may have a role followed by lymph node dissection in patients with a positive node. Published by Elsevier Inc.
Malignant eccrine spiradenoma (MES) is one of the rarest sweat-gland tumors and can arise from benign eccrine spiradenoma1 or, less commonly, develop de novo. The latency period before transformation into malignant disease can range from 6 months to 70 years.2 A total of 102 cases of MES have been reported in the English literature. Current reports suggest that the tumor predominates in older patients, with minimal gender predilection.3 Benign eccrine spiradenoma usually presents as a painful, slow-growing, 1 to 2-cm nodule underneath the epidermis on the head or upper trunk.4 The typical manifestation of MES is a chronic skin mass with recent rapid growth, which may show erythema, tenderness, ulceration, bleeding, * Corresponding author. Tel.: ⫹1-857-203-6205; fax: ⫹1-857-203-5549. E-mail address: [email protected] Manuscript received February 5, 2010; revised manuscript April 7, 2010
0002-9610/$ - see front matter Published by Elsevier Inc. doi:10.1016/j.amjsurg.2010.04.015
and satellite nodules. The appearance of this tumor varies but may resemble melanoma5 or an epidermal inclusion cyst6 on initial physical examination. On pathologic examination of MES, glandular patterns can be seen. Morphologic differentiation is variable, occasionally with near-complete loss of eccrine differentiation. Consequently, the diagnosis often relies on adjacent benign spiradenoma tissue displaying the characteristic appearance. Accordingly, extensive sampling to look for a potential benign component may be necessary. The classic histopathology of MES shows solid islands of anaplastic basaloid cells arranged in cords and nodules, with highly pleomorphic cells containing abundant mitotic figures. These cells may express cytokeratins, epithelial membrane antigen,5 p53, S100, and carcinoembryonic antigen.4 Malignant transformation often includes infringement of tumor cells into adjacent stroma. Metastasis usually involves lymph nodes before further spread. Common sites of distal metastasis for this aggres-
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The American Journal of Surgery, Vol 201, No 5, May 2011
sive neoplasm include regional lymph nodes, lung, liver, brain, spinal cord, bone, and skin. Although there is no established treatment regimen, wide resection with 1-cm, tumor-free, circumferential and deep margins down to the fascia has been advocated.3 Alternatively, Mohs micrographic surgery also has been described.3 Elective lymph node dissection is questionable,3 and sentinel node excision might be an alternative option.7,8 The efficacy of adjuvant therapy is unknown, and radiation therapy might have a role in reducing local recurrence.9 Chemotherapeutic agents such as methotrexate, cisplatin, etoposide, and 5-fluorouracil have been used with limited success.10 –13 Because this tumor is so uncommon, only individual cases and small series have been reported. Because of the paucity of data to date, there has been no detailed survival analysis or consensus on the proper treatment of this malignancy. This study presents a meta-analysis of previously reported patients regarding the natural course and most effective treatment of MES.
tics as in traditional meta-analysis methodology. Studies were analyzed by institution and author to ensure that patients were not duplicated. Four patients who died of other causes (postoperative complications of an unrelated orthopedic surgery,48 pre-existing metastatic adenocarcinoma of the colon,47 stroke,21 and pre-existing chronic myelogenous leukemia18) were removed from the survival analysis. Patient survival prognosis was analyzed according to status of metastasis at presentation (lymph node negative, lymph node positive, and distant metastasis) with a Kaplan–Meier survival curve. Similarly, overall treatment modalities (local resection with or without an adjuvant therapy such as chemotherapy or radiotherapy) were compared with Kaplan– Meier survival curve analysis. A test result with a P value of less than .05 was considered significant.
Methods The MEDLINE database was searched for all Englishlanguage articles containing the keyword “eccrine spiradenoma” and any relevant cited references, which yielded 61 journal articles,1– 8,10 – 61 comprising 102 cases of MES as diagnosed by the original authors. Seventy-two reported cases provided sufficient data resolution (including treatment modality, follow-up time, and survival status at final follow-up evaluation) to perform a 1-stage individual patient data meta-analysis with GraphPad Prism software (La Jolla, CA), using methods previously described and validated.62 The 1-stage individual patient data meta-analysis statistical approach pools all published raw patient data as if all patients belonged to a single cohort to perform a survival analysis, instead of basing calculations on summary statis-
Table 1
Results Treatment modalities and outcomes are summarized in Table 1. The presence of lymph node or distant metastasis of MES significantly reduced survival (P ⬍ .0001; Fig. 1). The overwhelming majority of nonmetastatic disease with no known lymph node involvement was treated with local resection, with 3 patients undergoing additional lymph node dissections. Of 36 total cases of nonmetastatic disease, the 35 patients treated with local surgical resection alone yielded a disease-free survival rate of 100% with a mean follow-up period of 33 months (standard deviation, 39 mo; range, 6 –144 mo). The remaining patient underwent an incomplete superficial excision for initial treatment because the etiology of the tumor was not fully understood at that time. The persistent locoregional disease was later treated unsuccessfully with radiotherapy, necessitating a subsequent more radical surgical intervention 10 months later to remove the residual tumor.
Summary of patient treatments and outcomes
Local disease Total patients No evidence of disease Alive with disease Died of disease Lymph node metastasis Total patients No evidence of disease Alive with disease Died of disease Distant metastasis Total patients No evidence of disease Alive with disease Died of disease
Local resection
Lymph node dissection
Chemotherapy
Radiotherapy
Chemoradiotherapy
32 32 0 0
3 3 0 0
0 0 0 0
1 0 1 0
0 0 0 0
5 2 0 3
7 6 1 0
0 0 0 0
0 0 0 0
0 0 0 0
12 2 1 9
1 0 0 1
3 0 0 3
5 2 0 3
3 0 1 2
M.T. Andreoli and K.M.F. Itani
Malignant eccrine spiradenoma
Figure 1 Malignant eccrine spiradenoma survival. Pooled results of patients with varying degrees of metastasis are evaluated using a Kaplan–Meier curve. There was a significant difference in survival between all groups.
Twelve patients showed lymph node metastasis without distant metastasis. All of these patients underwent surgical resection of the tumor, with 7 patients receiving additional lymph node dissection. Of the 12 total patients, 3 patients without lymph node dissection died of metastatic disease (mean survival, 45 mo; standard deviation, 6 mo; range, 39 – 49 mo); 1 patient was alive with disease 24 months after lymph node dissection; and 8 patients (6 of whom underwent lymph node dissection) lacked evidence of recurrent disease at final follow-up evaluation (mean, 47 mo; standard deviation, 36 mo; range, 2–97 mo). Twenty-four patients presented with distant metastasis (Fig. 2), with a median survival of 16 months. The treatments varied widely in this subset of patients: 13 patients underwent local resection (1 patient underwent lymph node dissection in addition) and 11 were given adjuvant therapy in addition to surgery. These adjuvant modalities included 5 instances of radiotherapy alone, 3 cases of chemotherapy alone, and 3 occurrences of chemoradiotherapy. The median survival time for the surgical group was 12 months. Surgery with adjuvant therapy yielded a median survival time of 20 months. However, the survival curve did not significantly differ between the surgery and surgery plus adjuvant therapy treatment groups (P ⫽ .8763; hazard ratio, 1.08; 95% confidence interval, .42–2.79).
697 However, in view of the frequent lymph node metastasis and the disease-free survival in 6 of 7 patients undergoing lymph node dissection for lymph node involvement (Table 1), an aggressive surgical approach to the corresponding lymph node basin is advocated. Although sentinel node biopsy only recently has been used for this entity,7,8 this procedure may benefit patients with clinically absent lymph node involvement. In the case of a positive sentinel node or clinically positive nodes, lymph node dissection of the corresponding lymph node basin might slow the progress of disease, as seen in the 1 patient alive with disease 24 months after lymph node dissection. As for surgical margins, recommendations can follow those of melanoma, which has a larger dataset from which to draw recommendations. Based on our analysis, no definitive statement can be made regarding adjuvant therapy in patients without distant disease. The only patient without metastasis at presentation that showed persistent local disease was treated with radiotherapy; this patient remained alive with disease until definitive surgical intervention was performed. In the case of distant metastasis, the median survival time was longer for patients treated with adjuvant therapy than with local resection alone, but this outcome was not statistically significant. Although the lack of significance may be due to the scarcity of data, these results do not show a survival advantage for systemic adjuvant therapy over surgical resection in this situation. Additional surgery with or without adjuvant therapy to address metastatic disease should be studied and discussed with each patient while placing overall patient condition and performance status in perspective. The main shortcoming of this study was the limited sample size, as well as the lack of long-term follow-up evaluation. The rarity of this tumor does not lend itself to the design of a randomized controlled trial, and a metaanalysis is the most powerful tool to assess its natural course and best therapeutic approach. However, meta-analysis also is susceptible to biases introduced by reporting surgeons.
Comments The rarity and aggressive clinical course of eccrine spiradenoma warrant heightened awareness among surgeons likely to deal with this entity. The potential for benign to malignant transformation, de novo growth, and local or distant recurrence necessitates a recommendation for wide local excision and close follow-up evaluation of both the benign and malignant forms of this disease. This approach is supported by the course of 35 patients with no metastatic disease treated with local resection alone, resulting in a disease-free survival rate of 100% at 33 months (Table 1).
Figure 2 Metastatic malignant eccrine spiradenoma survival by treatment modality. Pooled results of patients with metastatic disease are compared by treatment modality using a Kaplan–Meier curve. There was no significant difference in survival between the local surgery and surgery with adjuvant therapy groups.
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The American Journal of Surgery, Vol 201, No 5, May 2011
We recommend a heightened awareness among surgeons to this disease entity in both the benign and malignant forms. An aggressive surgical approach is supported in patients with no metastasis. In the absence of clinical involvement of lymph nodes, a sentinel node biopsy may be useful, with lymph node dissection performed for patients with positive nodes. Adjuvant therapy might offer an advantage and warrants additional study.
22. Cooper PH, Frierson HF Jr, Morrison AG. Malignant transformation of eccrine spiradenoma. Arch Dermatol 1985;121:1445– 8. 23. Galadari E, Mehregan AH, Lee KC. Malignant transformation of eccrine tumors. J Cutan Pathol 1987;14:15–22. 24. Wick MR, Swanson PE, Kaye VN, et al. Sweat gland carcinoma ex eccrine spiradenoma. Am J Dermatopathol 1987;9:90 – 8. 25. Meriggi F, Tagliabo R, Morone G, et al. The potential malignancy of eccrine spiradenoma. Ital J Surg Sci 1989;19:265– 8. 26. Varsa EW, Jordan SW. Fine needle aspiration cytology of malignant spiradenoma arising in congenital eccrine spiradenoma. Acta Cytol 1990;34:275–7. 27. McKee PH, Fletcher CD, Stavrinos P, et al. Carcinosarcoma arising in eccrine spiradenoma. A clinicopathologic and immunohistochemical study of two cases. Am J Dermatopathol 1990;12:335– 43. 28. Nakamura S, Imai T, Nakayama K, et al. Malignant eccrine tumor—a case report and a classification of tumors of eccrine sweat apparatus. J Dermatol 1990;17:500 –5. 29. Zamboni AC, Zamboni WA, Ross DS. Malignant eccrine spiradenoma of the hand. J Surg Oncol 1990;43:131–3. 30. Engel CJ, Meads GE, Joseph NG, et al. Eccrine spiradenoma: a report of malignant transformation. Can J Surg 1991;34:477– 80. 31. Husek K, Plchova M, Samohyl J. [Malignant transformation in multiple eccrine spiradenoma]. Cesk Patol 1992;28:48 –52. 32. Argenyi ZB, Nguyen AV, Balogh K, et al. Malignant eccrine spiradenoma. A clinicopathologic study. Am J Dermatopathol 1992;14:381– 90. 33. Dijkhuizen T, van den Berg E, Nikkels PG, et al. Cytogenetics of a case of eccrine spiradenoma. Hum Pathol 1992;23:1085–7. 34. Malhotra RW, Wilbum S, Patwardhan N, et al. Malignant eccrine spiradenomas with hemangiomatous elements: DNA ploidy, light microscopy, and immunohistochemical studies of two cases. J Cutan Pathol 1993;20:555. 35. Thomas B, Duwel V, Proot L, et al. An uncommon breast tumour: the malignant eccrine spiradenoma. A case report. Acta Chir Belg 1993; 93:295– 8. 36. Pontone M, Potter GK, Berlin SJ, et al. Malignant eccrine neoplasms of the foot. J Foot Ankle Surg 1994;33:486 –91. 37. Huerre M, Bonnet D, Mc Carthy SW, et al. [Carcinosarcoma arising in eccrine spiradenoma. A morphologic and immunohistochemical study]. Ann Pathol 1994;14:168 –73. 38. Herzberg AJ, Elenitsas R, Strohmeyer CR. An unusual case of early malignant transformation in a spiradenoma. Dermatol Surg 1995;21: 731– 4. 39. Saboorian MH, Kenny M, Ashfaq R, et al. Carcinosarcoma arising in eccrine spiradenoma of the breast. Report of a case and review of the literature. Arch Pathol Lab Med 1996;120:501– 4. 40. Itoh T, Yamamoto N, Tokunaga M. Malignant eccrine spiradenoma with smooth muscle cell differentiation: histological and immunohistochemical study. Pathol Int 1996;46:887–93. 41. McCluggage WG, Fon LJ, O’Rourke D, et al. Malignant eccrine spiradenoma with carcinomatous and sarcomatous elements. J Clin Pathol 1997;50:871–3. 42. Lee HH, Lee KG. Malignant eccrine spiradenoma with florid squamous differentiation. J Korean Med Sci 1998;13:191–5. 43. Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years. J Am Acad Dermatol 1998;38:960 – 6. 44. Jamshidi M, Nowak MA, Chiu YT, et al. Giant malignant eccrine spiradenoma of the scalp. Dermatol Surg 1999;25:45– 8. 45. Sonmez Ergun S, Balsever Kural Y, Buyukbabani N. Guess what! Malignant eccrine spiradenoma. Eur J Dermatol 2000;10:65–7. 46. Granter SR, Seeger K, Calonje E, et al. Malignant eccrine spiradenoma (spiradenocarcinoma): a clinicopathologic study of 12 cases. Am J Dermatopathol 2000;22:97–103. 47. Yildirim S, Akoz T, Akan M, et al. Malignant eccrine spiradenoma with an interesting and unusual location. Dermatol Surg 2001;27:417–20.
References 1. Dabska M. Malignant transformation of eccrine spiradenoma. Pol Med J 1972;11:388 –96. 2. Ribeiro-Silva A, Shaletich C, Careta RS, et al. Spiradenocarcinoma of the breast arising in a long-standing spiradenoma. Ann Diagn Pathol 2004;8:162– 6. 3. Hantash BM, Chan JL, Egbert BM, et al. De novo malignant eccrine spiradenoma: a case report and review of the literature. Dermatol Surg 2006;32:1189 –98. 4. Tanaka Y, Bhunchet E, Shibata T. A case of malignant eccrine spiradenoma metastatic to intramammary lymph node. Breast Cancer 2008;15:175– 80. 5. Tanese K, Sato T, Ishiko A. Malignant eccrine spiradenoma: case report and review of the literature, including 15 Japanese cases. Clin Exp Dermatol 2009;35:51–5. 6. Beekley AC, Brown TA, Porter C. Malignant eccrine spiradenoma: a previously unreported presentation and review of the literature. Am Surg 1999;65:236 – 40. 7. Seyhan T, Borman H, Bal N. Malignant eccrine spiradenoma of the scalp. J Craniofac Surg 2008;19:1608 –12. 8. Chase DM, Basu T, Saffari B, et al. Malignant eccrine spiradenoma of the vulva: a case report and review of the literature. Int J Gynecol Cancer 2006;16:1465–9. 9. Agarwal S, Khanna R, Arya NC, et al. Malignant eccrine spiradenoma: an unusual presentation. Indian J Dermatol Venereol Leprol 2002;68: 290 –1. 10. Tay JS, Tapen EM, Solari PG. Malignant eccrine spiradenoma. Case report and review of the literature. Am J Clin Oncol 1997;20:552–7. 11. Ishikawa M, Nakanishi Y, Yamazaki N, et al. Malignant eccrine spiradenoma: a case report and review of the literature. Dermatol Surg 2001;27:67–70. 12. Sridhar KS, Benedetto P, Otrakji CL, et al. Response of eccrine adenocarcinoma to tamoxifen. Cancer 1989;64:366 –70. 13. Morris DM, Sanusi ID, Lanehart WH. Carcinoma of eccrine sweat gland: experience with chemotherapy, autopsy findings in a patient with metastatic eccrine carcinoma, and a review of the literature. J Surg Oncol 1986;31:26 –30. 14. Kersting DW, Helwig EB. Eccrine spiradenoma. AMA Arch Derm 1956;73:199 –227. 15. Lucas GL, Nordby EJ. Sweat gland carcinoma of the hand. Hand 1974;6:98 –102. 16. Grizzard WS, Torezynski E, Edwards WC. Adenocarcinoma of eccrine sweat glands. Arch Ophthalmol 1976;94:2119 –23. 17. Evans HL, Su D, Smith JL, et al. Carcinoma arising in eccrine spiradenoma. Cancer 1979;43:1881– 4. 18. Mambo NC. Eccrine spiradenoma: clinical and pathologic study of 49 tumors. J Cutan Pathol 1983;10:312–20. 19. Okada N, Ota J, Sato K, et al. Metastasizing eccrine sweat gland carcinoma. Report of a case. Arch Dermatol 1984;120:768 –9. 20. Yaremchuk MJ, Elias LS, Graham RR, et al. Sweat gland carcinoma of the hand: two cases of malignant eccrine spiradenoma. J Hand Surg 1984;9:910 – 4. 21. Wick MR, Goellner JR, Wolfe JT 3rd, et al. Adnexal carcinomas of the skin. I. Eccrine carcinomas. Cancer 1985;56:1147– 62.
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Malignant eccrine spiradenoma
48. Fernandez-Acenero MJ, Manzarbeitia F, Mestre de Juan MJ, et al. Malignant spiradenoma: report of two cases and literature review. J Am Acad Dermatol 2001;44:395– 8. 49. Lara JF, Nadeem MA, Asaadi M. Malignant mixed tumor ex eccrine spiradenoma: an unusual pattern of malignant dedifferentiation. Ann Diagn Pathol 2001;5:155– 61. 50. Otero-Garcia JE, Carlo VJ, Trinidad-Pinedo J. Malignant eccrine spiradenoma of the neck: a case report. Otolaryngol Head Neck Surg 2001;125:428. 51. Arslan E, Unal S, Cinel L, et al. Malignant eccrine spiradenoma occurring on a traumatized area. Plast Reconstr Surg 2002;110:365–7. 52. Mirza I, Kloss R, Sieber SC. Malignant eccrine spiradenoma. Arch Pathol Lab Med 2002;126:591– 4. 53. Roetman B, Vakilzadeh F, Krismann M. [Eccrine spiradenocarcinoma with unusual histiocytic giant cell components. Case report and review of the literature of a rare sweat gland tumor]. Pathologe 2002;23:149 –55. 54. Russ BW, Meffert J, Bernert R. Spiradenocarcinoma of the scalp. Cutis 2002;69:455– 8. 55. Rege JD, Aditya GS, Shet TM. Fine needle aspiration cytology of extramedullary plasmacytoma. Acta Cytol 2002;46:789 –90.
699 56. Kelly BT, Kadrmas WR, Gayle L, et al. Extensor mechanism reconstruction after wide excision of a malignant eccrine spiradenocarcinoma of the patellar tendon. J Knee Surg 2002;15:161– 4. 57. Meyer TK, Rhee JS, Smith MM, et al. External auditory canal eccrine spiradenocarcinoma: a case report and review of literature. Head Neck 2003;25:505–10. 58. Leonard N, Smith D, McNamara P. Low-grade malignant eccrine spiradenoma with systemic metastases. Am J Dermatopathol 2003;25: 253–5. 59. Chou SC, Lin SL, Tseng HH. Malignant eccrine spiradenoma: a case report with pulmonary metastasis. Pathol Int 2004;54:208 –12. 60. Ben Brahim E, Sfia M, Tangour M, et al. Malignant eccrine spiradenoma: a new case report. J Cutan Pathol 2009;37:478 – 81. 61. Delfino S, Toto V, Brunetti B, et al. Recurrent atypical eccrine spiradenoma of the forehead. In Vivo 2008;22:821–3. 62. Koopman L, van der Heijden GJ, Hoes AW, et al. Empirical comparison of subgroup effects in conventional and individual patient data meta-analyses. Int J Technol Assess Health Care 2008;24: 358 – 61.
Reviews
Malignant eccrine spiradenoma: a meta-analysis of reported cases Michael T. Andreoli, B.A.a, Kamal M.F. Itani, M.D.a,b,* a
Boston University, Boston, MA, USA; bDepartment of Surgery, Boston Veterans Affairs Health Care System, 1400 VFW Parkway, 112A, West Roxbury, MA 02132, USA KEYWORDS: Malignant; Eccrine; Spiradenoma; Spiradenocarcinoma; Appendageal; Tumor
Abstract BACKGROUND: Malignant eccrine spiradenoma is an aggressive sweat gland tumor with poorly understood behavior and no currently accepted therapeutic regimen. METHODS: An individual patient data meta-analysis with Kaplan–Meier survival curves was performed on 72 reported cases of malignant eccrine spiradenoma. RESULTS: In 35 patients with no distant metastasis, local resection resulted in 100% disease-free survival. Of 7 patients with lymph node but no distant metastasis treated with surgical resection and lymph node dissection, 6 patients remained disease-free at final follow-up evaluation. For the 24 cases with confirmed distant metastatic disease, patient survival did not significantly differ between local resection and surgery with adjuvant chemoradiotherapy (P ⫽ .8763). CONCLUSIONS: Heightened awareness is recommended among surgeons likely to treat this entity. An aggressive surgical approach is supported in the absence of metastasis. When lymph nodes are not clinically involved, sentinel node may have a role followed by lymph node dissection in patients with a positive node. Published by Elsevier Inc.
Malignant eccrine spiradenoma (MES) is one of the rarest sweat-gland tumors and can arise from benign eccrine spiradenoma1 or, less commonly, develop de novo. The latency period before transformation into malignant disease can range from 6 months to 70 years.2 A total of 102 cases of MES have been reported in the English literature. Current reports suggest that the tumor predominates in older patients, with minimal gender predilection.3 Benign eccrine spiradenoma usually presents as a painful, slow-growing, 1 to 2-cm nodule underneath the epidermis on the head or upper trunk.4 The typical manifestation of MES is a chronic skin mass with recent rapid growth, which may show erythema, tenderness, ulceration, bleeding, * Corresponding author. Tel.: ⫹1-857-203-6205; fax: ⫹1-857-203-5549. E-mail address: [email protected] Manuscript received February 5, 2010; revised manuscript April 7, 2010
0002-9610/$ - see front matter Published by Elsevier Inc. doi:10.1016/j.amjsurg.2010.04.015
and satellite nodules. The appearance of this tumor varies but may resemble melanoma5 or an epidermal inclusion cyst6 on initial physical examination. On pathologic examination of MES, glandular patterns can be seen. Morphologic differentiation is variable, occasionally with near-complete loss of eccrine differentiation. Consequently, the diagnosis often relies on adjacent benign spiradenoma tissue displaying the characteristic appearance. Accordingly, extensive sampling to look for a potential benign component may be necessary. The classic histopathology of MES shows solid islands of anaplastic basaloid cells arranged in cords and nodules, with highly pleomorphic cells containing abundant mitotic figures. These cells may express cytokeratins, epithelial membrane antigen,5 p53, S100, and carcinoembryonic antigen.4 Malignant transformation often includes infringement of tumor cells into adjacent stroma. Metastasis usually involves lymph nodes before further spread. Common sites of distal metastasis for this aggres-
696
The American Journal of Surgery, Vol 201, No 5, May 2011
sive neoplasm include regional lymph nodes, lung, liver, brain, spinal cord, bone, and skin. Although there is no established treatment regimen, wide resection with 1-cm, tumor-free, circumferential and deep margins down to the fascia has been advocated.3 Alternatively, Mohs micrographic surgery also has been described.3 Elective lymph node dissection is questionable,3 and sentinel node excision might be an alternative option.7,8 The efficacy of adjuvant therapy is unknown, and radiation therapy might have a role in reducing local recurrence.9 Chemotherapeutic agents such as methotrexate, cisplatin, etoposide, and 5-fluorouracil have been used with limited success.10 –13 Because this tumor is so uncommon, only individual cases and small series have been reported. Because of the paucity of data to date, there has been no detailed survival analysis or consensus on the proper treatment of this malignancy. This study presents a meta-analysis of previously reported patients regarding the natural course and most effective treatment of MES.
tics as in traditional meta-analysis methodology. Studies were analyzed by institution and author to ensure that patients were not duplicated. Four patients who died of other causes (postoperative complications of an unrelated orthopedic surgery,48 pre-existing metastatic adenocarcinoma of the colon,47 stroke,21 and pre-existing chronic myelogenous leukemia18) were removed from the survival analysis. Patient survival prognosis was analyzed according to status of metastasis at presentation (lymph node negative, lymph node positive, and distant metastasis) with a Kaplan–Meier survival curve. Similarly, overall treatment modalities (local resection with or without an adjuvant therapy such as chemotherapy or radiotherapy) were compared with Kaplan– Meier survival curve analysis. A test result with a P value of less than .05 was considered significant.
Methods The MEDLINE database was searched for all Englishlanguage articles containing the keyword “eccrine spiradenoma” and any relevant cited references, which yielded 61 journal articles,1– 8,10 – 61 comprising 102 cases of MES as diagnosed by the original authors. Seventy-two reported cases provided sufficient data resolution (including treatment modality, follow-up time, and survival status at final follow-up evaluation) to perform a 1-stage individual patient data meta-analysis with GraphPad Prism software (La Jolla, CA), using methods previously described and validated.62 The 1-stage individual patient data meta-analysis statistical approach pools all published raw patient data as if all patients belonged to a single cohort to perform a survival analysis, instead of basing calculations on summary statis-
Table 1
Results Treatment modalities and outcomes are summarized in Table 1. The presence of lymph node or distant metastasis of MES significantly reduced survival (P ⬍ .0001; Fig. 1). The overwhelming majority of nonmetastatic disease with no known lymph node involvement was treated with local resection, with 3 patients undergoing additional lymph node dissections. Of 36 total cases of nonmetastatic disease, the 35 patients treated with local surgical resection alone yielded a disease-free survival rate of 100% with a mean follow-up period of 33 months (standard deviation, 39 mo; range, 6 –144 mo). The remaining patient underwent an incomplete superficial excision for initial treatment because the etiology of the tumor was not fully understood at that time. The persistent locoregional disease was later treated unsuccessfully with radiotherapy, necessitating a subsequent more radical surgical intervention 10 months later to remove the residual tumor.
Summary of patient treatments and outcomes
Local disease Total patients No evidence of disease Alive with disease Died of disease Lymph node metastasis Total patients No evidence of disease Alive with disease Died of disease Distant metastasis Total patients No evidence of disease Alive with disease Died of disease
Local resection
Lymph node dissection
Chemotherapy
Radiotherapy
Chemoradiotherapy
32 32 0 0
3 3 0 0
0 0 0 0
1 0 1 0
0 0 0 0
5 2 0 3
7 6 1 0
0 0 0 0
0 0 0 0
0 0 0 0
12 2 1 9
1 0 0 1
3 0 0 3
5 2 0 3
3 0 1 2
M.T. Andreoli and K.M.F. Itani
Malignant eccrine spiradenoma
Figure 1 Malignant eccrine spiradenoma survival. Pooled results of patients with varying degrees of metastasis are evaluated using a Kaplan–Meier curve. There was a significant difference in survival between all groups.
Twelve patients showed lymph node metastasis without distant metastasis. All of these patients underwent surgical resection of the tumor, with 7 patients receiving additional lymph node dissection. Of the 12 total patients, 3 patients without lymph node dissection died of metastatic disease (mean survival, 45 mo; standard deviation, 6 mo; range, 39 – 49 mo); 1 patient was alive with disease 24 months after lymph node dissection; and 8 patients (6 of whom underwent lymph node dissection) lacked evidence of recurrent disease at final follow-up evaluation (mean, 47 mo; standard deviation, 36 mo; range, 2–97 mo). Twenty-four patients presented with distant metastasis (Fig. 2), with a median survival of 16 months. The treatments varied widely in this subset of patients: 13 patients underwent local resection (1 patient underwent lymph node dissection in addition) and 11 were given adjuvant therapy in addition to surgery. These adjuvant modalities included 5 instances of radiotherapy alone, 3 cases of chemotherapy alone, and 3 occurrences of chemoradiotherapy. The median survival time for the surgical group was 12 months. Surgery with adjuvant therapy yielded a median survival time of 20 months. However, the survival curve did not significantly differ between the surgery and surgery plus adjuvant therapy treatment groups (P ⫽ .8763; hazard ratio, 1.08; 95% confidence interval, .42–2.79).
697 However, in view of the frequent lymph node metastasis and the disease-free survival in 6 of 7 patients undergoing lymph node dissection for lymph node involvement (Table 1), an aggressive surgical approach to the corresponding lymph node basin is advocated. Although sentinel node biopsy only recently has been used for this entity,7,8 this procedure may benefit patients with clinically absent lymph node involvement. In the case of a positive sentinel node or clinically positive nodes, lymph node dissection of the corresponding lymph node basin might slow the progress of disease, as seen in the 1 patient alive with disease 24 months after lymph node dissection. As for surgical margins, recommendations can follow those of melanoma, which has a larger dataset from which to draw recommendations. Based on our analysis, no definitive statement can be made regarding adjuvant therapy in patients without distant disease. The only patient without metastasis at presentation that showed persistent local disease was treated with radiotherapy; this patient remained alive with disease until definitive surgical intervention was performed. In the case of distant metastasis, the median survival time was longer for patients treated with adjuvant therapy than with local resection alone, but this outcome was not statistically significant. Although the lack of significance may be due to the scarcity of data, these results do not show a survival advantage for systemic adjuvant therapy over surgical resection in this situation. Additional surgery with or without adjuvant therapy to address metastatic disease should be studied and discussed with each patient while placing overall patient condition and performance status in perspective. The main shortcoming of this study was the limited sample size, as well as the lack of long-term follow-up evaluation. The rarity of this tumor does not lend itself to the design of a randomized controlled trial, and a metaanalysis is the most powerful tool to assess its natural course and best therapeutic approach. However, meta-analysis also is susceptible to biases introduced by reporting surgeons.
Comments The rarity and aggressive clinical course of eccrine spiradenoma warrant heightened awareness among surgeons likely to deal with this entity. The potential for benign to malignant transformation, de novo growth, and local or distant recurrence necessitates a recommendation for wide local excision and close follow-up evaluation of both the benign and malignant forms of this disease. This approach is supported by the course of 35 patients with no metastatic disease treated with local resection alone, resulting in a disease-free survival rate of 100% at 33 months (Table 1).
Figure 2 Metastatic malignant eccrine spiradenoma survival by treatment modality. Pooled results of patients with metastatic disease are compared by treatment modality using a Kaplan–Meier curve. There was no significant difference in survival between the local surgery and surgery with adjuvant therapy groups.
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We recommend a heightened awareness among surgeons to this disease entity in both the benign and malignant forms. An aggressive surgical approach is supported in patients with no metastasis. In the absence of clinical involvement of lymph nodes, a sentinel node biopsy may be useful, with lymph node dissection performed for patients with positive nodes. Adjuvant therapy might offer an advantage and warrants additional study.
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