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Comparison of Mohs Micrographic Surgery and Wide Excision for Extramammary Paget's Disease

Background. Extramammary Paget's disease is a rare cutaneous adenocarcinoma that occurs in an apocrine gland distribution mainly in the anogenital region.Objective. To formulate treatment recommendations for this rare disease, we examined
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  Comparison of Mohs Micrographic Surgery and WideExcision for Extramammary Paget’s Disease W ILLIAM  J. O’C ONNOR , MD, n K ATHERINE  K. L IM , MD, n M ARK  J. Z ALLA , MD, n M AUREEN . G AGNOT , HT, n C LARK  C. O TLEY , MD, w T RI  H. N GUYEN , MD, w AND R ANDALL  K. R OENIGK , MD w n Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, and   w Mayo Clinic, Rochester, Minnesota BACKGROUND.  Extramammary Paget’s disease is a rare cuta-neous adenocarcinoma that occurs in an apocrine glanddistribution mainly in the anogenital region. OBJECTIVE.  To formulate treatment recommendations for thisrare disease, we examined clinical and follow-up data of patients with it. METHODS.  A retrospective review is given about the treatmentand outcome for 95 patients at Mayo Clinic, Rochester,Minnesota, and Scottsdale, Arizona, between 1976 and 2001.The literature regarding diagnosis and treatment of this diseaseis also reviewed. RESULTS.  Of the 95 patients, 86 had primary disease and 9 hadrecurrent disease. At mean follow-up (wide excision, 65months; Mohs surgery, 24 months), disease had recurred in18 of 83 (22%) who underwent standard wide excision,compared with recurrence in 1 of 12 (8%) who had the Mohsmicrographic excision. CONCLUSION.  Mohs micrographic surgery compares favorablywith wide excision. Intraoperative immunostaining with cyto-keratin 7 is helpful in delineating disease, as are preoperativescouting biopsies and photodynamic diagnosis. W. J. O’CONNOR, MD, K. K. LIM, MD, M. J. ZALLA, MD, M. M. GAGNOT, HT, C. C. OTLEY, MD, T. H. NGUYEN, MD,AND R. K. ROENIGK, MD HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS. EXTRAMAMMARY PAGET’S disease is a rarecutaneous adenocarcinoma that occurs in an apocrinegland distribution. The most commonly affected sitesare the vulva, penis, scrotum, anal and perianal area,axilla, and umbilicus. Rarer sites include the eyelid,external auditory canal, truncal skin, and cheek. 1 Extramammary Paget’s disease may occur as a primaryprocess or as epidermotropic metastases from anunderlying contiguous gastrointestinal or genitourin-ary carcinoma or from a noncontiguous carcinoma. 2 Thus, extensive evaluation of patients at presentationis mandatory.Clinically, extramammary Paget’s disease is char-acterized by a red, moist, eroded plaque, typically inthe anogenital region (Figure 1). Itch and discomfortare common symptoms. A delay in diagnosis of 5 to 10years before a biopsy is performed is not unusual. 3 Often, the disease is misdiagnosed and treated as ‘‘jockitch.’’ Occasionally, it occurs multicentrically, andtriple extramammary Paget’s disease that involvesboth axillae as well as the perineum has beendescribed. 4 Evaluation of the axilla is recommendedat initial presentation.The tumor behaves as a slow-growing intraepithe-lial adenocarcinoma. However, it may become inva-sive, and dermal tumor nests may metastasize throughdermal lymphatics. As many as 10% of patients withextramammary Paget’s disease may have lymph nodeinvolvement at presentation, but whether sentinellymph node biopsy is useful is not known.A typical pattern of erythema (‘‘underpants pat-tern’’) has been described as indicating dermalmetastases. 5 Patients with metastatic extramammaryPaget’s disease are poor surgical candidates, and theyhave a mean survival of only 13 months.Histopathology shows epidermal acanthosis orhyperkeratosis. Paget’s cells are large round cells withabundant pale staining cytoplasm and a large centralreticulated nucleus. Frequent mitotic figures may befound. Paget’s cells may appear singly or scattered inclusters throughout the epidermis (Figure 2).Immunohistochemistry is important to confirm thediagnosis of extramammary Paget’s disease. Cytoker-atin is a structural component for cytoskeleton that isexpressed in poorly differentiated neoplasms of epithelial srcin. Paget’s cells stain positive with lowmolecular weight keratin. Cytokeratin 7 has beenreported as the immunostain of choice for evaluatingpermanent section margins of this tumor. 6 Immuno-phenotypes other than cytokeratin 7 1  /cytokeratin r  2003 by the American Society for Dermatologic Surgery, Inc.    Published by Blackwell Publishing, Inc. ISSN: 1076-0512/03/$15.00/0    Dermatol Surg 2003;29:723–727  Address correspondence to: William J. O’Connor, MD, Department of Dermatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ85259.  20– in Paget’s cells suggest underlying regional internalmalignancy. 7 The Ras oncogene  P21  also may be amarker of invasive disease.Carcinoembryonic antigen, 8 epithelial membraneantibody, and gross cystic disease fluid protein alsomay be positive. However, S-100 is negative. Thecytoplasm also contains mucin and thus is positive toperiodic acid-Schiff stain and resistant to diastase, andit stains with alcian blue at pH 2.5. Other mucinstains, such as colloidal iron and mucicarmine, are alsopositive. Clinically, the tumor has indistinct margins,and this leads to high recurrence rates.Treatment options include topical 5-fluorouracil 9 and topical bleomycin sulfate; radiation therapy, 10 cryotherapy, and chemotherapy; and CO 2  laser 11 therapy and photodynamic therapy. 12,13 However,topical 5-fluorouracil, CO 2  laser, cryotherapy, andradiation therapy are particularly painful in the groinarea. Wide excision has high recurrence rates of up to44%. 3 Considerable morbidity is associated withradical vulvectomies, scrotectomies, orchiectomies,and penectomies. Recently, topical imiquimod hasbeen reported to be a useful treatment modality. 14,15 Mohs micrographic excision does have theoreticaladvantages for this type of tumor, which has clinicallyindistinct margins, subclinical extension, high localrecurrence rates, and potential for metastasis. Tissuepreservation is also important because the tumor oftenencroaches on vital structures. 16,17 Preoperative topi-cal 5-fluorouracil has been used to delineate the extentof the disease. 18 Methods To formulate treatment recommendations for this raredisease, we conducted a retrospective review of out-come for 95 patients after surgical treatment of extramammary Paget’s disease during a 25-year periodbetween 1976 and 2001 at the Mayo Clinic (Roche-ster, Minnesota, and Scottsdale, Arizona). The studywas approved by the Mayo Foundation InstitutionalReview Board. The factors studied included age,gender, tumor site, whether tumor was primary orrecurrent, and associated neoplasms. We examinedoutcome after surgical treatment and followed asubgroup treated with Mohs micrographic excision. Figure1.  Patient with extensive extramammary Paget’s disease overthe left groin. (a)(b) Figure2.  Pagetoid cells in the epidermis. (a) Low power (hematox-ylin and eosin;   10). (b) Higher power (hematoxylin and eosin;  100). 724  O’CONNOR ET AL.: MOHS FOR PAGET’S DISEASE  Dermatol Surg 29:7:July 2003  We noted preoperative strategies to delineate tumorextent and methods of histologic margin assessment.Number of layers for clearance, postoperative defectsize, and method of repair were also noted. The datawere evaluated to formulate treatment recommenda-tions for this rare disease. Results Ninety-five patients (45 men and 50 women) withbiopsy-proved disease were studied. The mean age was70.4 years for the men and 69.8 years for the women(overall range, 53 to 87). Contiguous carcinoma wasfound in 19 of the 95 patients (20%). The mostcommon primary disease sites were the vulva, anal andperianal region, inguinal fold, scrotum, penis, andaxilla. The patient with axillary disease also hadsimultaneous disease in the perineum. Eighty-sixpatients had primary disease, and nine had recurrentdisease. Of the 83 treated with standard wide excision,with intraoperative vertical frozen section control,recurrent disease had occurred in 18 (22%) at follow-up (mean of 65 months). Urethral disease was notedfrequently, and some patients received CO 2  laser orradiation therapy after their surgical procedure.Twelve patients were treated with Mohs surgery,and in four, immunostains were used at the time of Mohs (Table 1). Cytokeratin 7 (Figure 3) was used infour patients, and carcinoembryonic antigen also wasused in two of these four patients.Preoperative scouting biopsies were performed infive patients. Photodynamic diagnosis was used in twopatients (Figure 4). Photodynamic therapy with  d -aminolevulinic acid (Levulan Kerastick) and Wood’slight 16 to 18 hours later also was attempted in onepatient.The length of follow-up was determined by clinicalexaminations or biopsy specimens recorded in thepatients’ medical record. At follow-up (mean of 24months), local disease had recurred in one Mohspatient (8%). A second patient died of metastaticadenocarcinoma of an unknown primary cause, whichraises the question of whether sentinel lymph nodebiopsy should be performed in advanced cases. Of those patients treated with Mohs surgery, one patientwas allowed to heal by second intention, and eight haddefects that were closed primarily, which emphasizesthat extensive laxity in the scrotum often allowsprimary repair despite large defects. Two patientsunderwent repair with a flap, and one patient had acombined flap full-thickness and split-thickness graft.Five patients required more than two layers. Two Table1 . Twelve Cases of Extramammary Paget’s Disease Treated With Mohs Patient Number Stain Layers n Preoperative Tumor Visualization Follow-up, Months Recurrence 1 Hematoxylin and eosin 4 72 No2 Carcinoembryonic antigen, cytokeratin 7 2 52 No3 Hematoxylin and eosin 2 S 51 No4 Hematoxylin and eosin 2 S 22 Metastaticadenocarcinoma5 Carcinoembryonic antigen 2 12 LocalCytokeratin 7 3Cytokeratin 7 3 Photodynamic diagnosis 18 No6 Cytokeratin 7 3 Photodynamic diagnosis 18 No7 Hematoxylin and eosin 1 S 12 No8 Hematoxylin and eosin 2 S 11 No9 Hematoxylin and eosin 1 10 No10 Hematoxylin and eosin 1 8 No11 Hematoxylin and eosin 7 1 3 7 No12 Hematoxylin and eosin 3 1 1 1 1 S 6 No S 5 preoperative scouting biopsy;  15 subsequent day(s) of Mohs. n Number of layers required for tumor removal on subsequent days of Mohs. Figure3.  Positive staining of extramammary Paget’s disease withintraoperative cytokeratin 7 at time of Mohs. Dermatol Surg 29:7:July 2003  O’CONNOR ET AL.: MOHS FOR PAGET’S DISEASE  725  (c) (e)(d)(a) (b) Figure4.  (a) Recurrent extramammary Paget’s disease after surgery and radiation therapy. (b) Topical 20% application of  d -aminolevulinic acid(Levulan Kerastick) to perineum. (c) Bright red fluorescence of extramammary Paget’s disease with Wood’s light examination 18 hours later, which ishelpful in guiding the first Mohs layer (d). (e) Primary closure after clearance. 726  O’CONNOR ET AL.: MOHS FOR PAGET’S DISEASE  Dermatol Surg 29:7:July 2003  patients had Mohs lasting more than 1 day. Thisreinforces the importance of preoperative tumorvisualization. Discussion The initial diagnosis of extramammary Paget’s diseaseis often delayed, and early biopsy should be consideredin patients with tinea cruris or erythrasma who areunresponsive to appropriate therapy. All patientsshould have a thorough work-up to exclude under-lying gastrointestinal, genitourinary, or internal malig-nancy. Immunophenotypes other than cytokeratin 7 1  / cytokeratin 20– in Paget’s cells suggest underlyingregional internal malignancy.Preoperative scouting biopsies may be helpful inplanning Mohs operations for patients with thisdisease. Shave biopsies are appropriate at the periph-ery of the tumor, but punch biopsy may be morehelpful at its center to evaluate the degree of adnexaland deeper dermal involvement. In advanced caseswith dermal involvement, sentinel lymph node biopsymay be a consideration. Photodynamic diagnosis usingtopical  d -aminolevulinic acid and Wood’s light 16 to18 hours later also may help delineate the extent of disease, as may preoperative topical 5-fluorouracil.Cytokeratin 7 is the immunostain of choice forintraoperative immunostaining. It is important to havea histotechnician who is experienced with the proces-sing of large tissue sections. Histologic discriminationbetween eccrine coil and dermal Paget’s disease mayalso be difficult on frozen sections, and a debulkinglayer for permanent sections with Mohs for theperipheral margin may be a useful option.Treating patients with this type of tumor requires amultidisciplinary approach that involves a colorectalsurgeon and a urologist in the work-up, because theirexpertise may be required in following any urethraland anal extensions of the disease and in repairingdefects in these areas. Preoperative 5-fluorouracil orphotodynamic diagnosis may be used to assesswhether extension to these structures has occurred.Photodynamic diagnosis may also be considered infollowing these patients because recurrences often lacksymptoms and are not visible clinically. A biopsyshould be performed if in doubt.We found that Mohs micrographic surgery com-pared favorably with wide excision and had a localrecurrence rate of 8% (at mean follow-up of 24months) versus 22% for patients who underwent wideexcision (at mean follow-up of 65 months). Longerfollow-up of these patients and a prospective study of a larger series of patients may provide additionalsupport for Mohs as an excellent treatment for thisdisease. Acknowledgments  Dr. O’Connor is the recipient of the 2001Theodore Tromovitch award for this article, which waspresented at the Mohs Meeting, Dallas, Texas, October2001. As a recipient of this award, Dr. O’Connor submittedhis article to  Dermatologic Surgery  for publication. References 1. Chilukuri S, Page R, Reed JA, Friedman J, Orengo I. Ectopicextramammary Paget’s disease arising on the cheek. Dermatol Surg2002;28:430–3.2. Chanda JJ. Extramammary Paget’s disease: prognosis and relation-ship to internal malignancy. J Am Acad Dermatol 1985;13:1009–14.3. Coldiron BM, Goldsmith BA, Robinson JK. Surgical treatment of extramammary Paget’s disease: a report of six cases and areexamination of Mohs micrographic surgery compared withconventional surgical excision. Cancer 1991;67:933–8.4. Kitajima S, Yamamoto K, Tsuji T, Schwartz RA. Triple extra-mammary Paget’s disease. Dermatol Surg 1997;23:1035–8.5. Murata Y, Kumano K, Tani M. Underpants-pattern erythema: apreviously unrecognized cutaneous manifestation of extramam-mary Paget’s disease of the genitalia with advanced metastaticspread. J Am Acad Dermatol 1999;40:949–56.6. Smith KJ, Tuur S, Corvette D, Lupton GP, Skelton HG. Cytokeratin7 staining in mammary and extramammary Paget’s disease. ModPathol 1997;10:1069–74.7. Ohnishi T, Watanabe S. The use of cytokeratins 7 and 20 in thediagnosis of primary and secondary extramammary Paget’s disease.Br J Dermatol 2000;142:243–7.8. Harris DW, Kist DA, Bloom K, Zachary CB. Rapid staining withcarcinoembryonic antigen aids limited excision of extramammaryPaget’s disease treated by Mohs surgery. J Dermatol Surg Oncol1994;20:260–4.9. Del Castillo LF, Garcia C, Schoendorgg C, et al. Spontaneousapparent clinical resolution with histologic persistence of a case of extramammary Paget’s disease: response to topical 5-fluorouracil.Cutis 2000;65:331–3.10. Moreno-Arias GA, Conill C, Castells-Mas A, Arenas M, Grimalt R.Radiotherapy for genital extramammary Paget’s disease in situ.Dermatol Surg 2001;27:587–90.11. Zollo JD, Zeitouni NC. The Roswell Park Cancer Instituteexperience with extramammary Paget’s disease. Br J Dermatol2000;142:59–65.12. Henta T, Itoh Y, Kobayashi M, Ninomiya Y, Ishibashi A.Photodynamic therapy for inoperable vulval Paget’s disease using d -aminolaevulinic acid:successful management of a large skinlesion. Br J Dermatol 1999;141:347–9.13. Shieh S, Dee AS, Cheney RT, et al. Photodynamic therapy for thetreatment of extramammary Paget’s disease. Br J Dermatol2002;146:1000–5.14. Zampogna JC, Flowers FP, Roth WI, Hassenein AM. Treatment of primary limited cutaneous extramammary Paget’s disease withtopical imiquimod monotherapy: two case reports. J Am AcadDermatol 2002;47(Suppl):229–35.15. Bamford J, Seidelmann S. Clinical and immunologic response of extramammary Paget’s disease to imiquimod [abstract]. J InvestDermatol 2001;117:537.16. Mohs FE, Blanchard L. Microscopically controlled surgery forextramammary Paget’s disease. Arch Dermatol 1979;115:706–8.17. Wagner RF Jr, Cottel WI. Treatment of extensive extramammaryPaget disease of male genitalia with Mohs micrographic surgery.Urology 1988;31:415–8.18. Eliezri YD, Silvers DN, Horan DB. Role of preoperative topical 5-fluorouracil in preparation for Mohs micrographic surgery of extramammary Paget’s disease. J Am Acad Dermatol 1987;17:497–505. Dermatol Surg 29:7:July 2003  O’CONNOR ET AL.: MOHS FOR PAGET’S DISEASE  727
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