Comparison of mohs micrographic surgery

At mean follow-up wide excision, 65 months; Mohs surgery, 24 months, disease had recurred in 18 of 83 22% who underwent standard wide excision, compared with recurrence in 1 of 12 8% who

Excision for Extramammary Paget’s Disease

WILLIAM J O’CONNOR, MD,n

KATHERINE K LIM, MD,n

MARK J ZALLA, MD,n

MAUREEN GAGNOT, HT,n

CLARK C OTLEY, MD,w TRI H NGUYEN, MD,w AND

RANDALL K ROENIGK, MDw

n

Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, andwMayo Clinic, Rochester, Minnesota

BACKGROUND Extramammary Paget’s disease is a rare

cuta-neous adenocarcinoma that occurs in an apocrine gland

distribution mainly in the anogenital region.

OBJECTIVE To formulate treatment recommendations for this

rare disease, we examined clinical and follow-up data of

patients with it.

METHODS A retrospective review is given about the treatment

and outcome for 95 patients at Mayo Clinic, Rochester,

Minnesota, and Scottsdale, Arizona, between 1976 and 2001.

The literature regarding diagnosis and treatment of this disease

is also reviewed.

RESULTS Of the 95 patients, 86 had primary disease and 9 had recurrent disease At mean follow-up (wide excision, 65 months; Mohs surgery, 24 months), disease had recurred in

18 of 83 (22%) who underwent standard wide excision, compared with recurrence in 1 of 12 (8%) who had the Mohs micrographic excision.

CONCLUSION Mohs micrographic surgery compares favorably with wide excision Intraoperative immunostaining with cyto-keratin 7 is helpful in delineating disease, as are preoperative scouting 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 rare

cutaneous adenocarcinoma that occurs in an apocrine

gland distribution The most commonly affected sites

are 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 primary

process or as epidermotropic metastases from an

underlying contiguous gastrointestinal or

genitourin-ary carcinoma or from a noncontiguous carcinoma.2

Thus, extensive evaluation of patients at presentation

is mandatory

Clinically, extramammary Paget’s disease is

char-acterized by a red, moist, eroded plaque, typically in

the anogenital region (Figure 1) Itch and discomfort

are common symptoms A delay in diagnosis of 5 to 10

years before a biopsy is performed is not unusual.3

Often, the disease is misdiagnosed and treated as ‘‘jock

itch.’’ Occasionally, it occurs multicentrically, and

triple extramammary Paget’s disease that involves

both axillae as well as the perineum has been

described.4 Evaluation of the axilla is recommended

at initial presentation

The tumor behaves as a slow-growing intraepithe-lial adenocarcinoma However, it may become inva-sive, and dermal tumor nests may metastasize through dermal lymphatics As many as 10% of patients with extramammary Paget’s disease may have lymph node involvement at presentation, but whether sentinel lymph node biopsy is useful is not known

A typical pattern of erythema (‘‘underpants pat-tern’’) has been described as indicating dermal metastases.5 Patients with metastatic extramammary Paget’s disease are poor surgical candidates, and they have a mean survival of only 13 months

Histopathology shows epidermal acanthosis or hyperkeratosis Paget’s cells are large round cells with abundant pale staining cytoplasm and a large central reticulated nucleus Frequent mitotic figures may be found Paget’s cells may appear singly or scattered in clusters throughout the epidermis (Figure 2)

Immunohistochemistry is important to confirm the diagnosis of extramammary Paget’s disease Cytoker-atin is a structural component for cytoskeleton that is expressed in poorly differentiated neoplasms of epithelial origin Paget’s cells stain positive with low molecular weight keratin Cytokeratin 7 has been reported as the immunostain of choice for evaluating permanent section margins of this tumor.6 Immuno-phenotypes other than cytokeratin 71/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, AZ

85259.

20– in Paget’s cells suggest underlying regional internal

malignancy.7 The Ras oncogene P21 also may be a

marker of invasive disease

Carcinoembryonic antigen,8 epithelial membrane

antibody, and gross cystic disease fluid protein also

may be positive However, S-100 is negative The

cytoplasm also contains mucin and thus is positive to

periodic acid-Schiff stain and resistant to diastase, and

it stains with alcian blue at pH 2.5 Other mucin

stains, such as colloidal iron and mucicarmine, are also

positive Clinically, the tumor has indistinct margins,

and this leads to high recurrence rates

Treatment options include topical 5-fluorouracil9

and topical bleomycin sulfate; radiation therapy,10

cryotherapy, and chemotherapy; and CO2 laser11

therapy and photodynamic therapy.12,13 However,

topical 5-fluorouracil, CO2 laser, cryotherapy, and

radiation therapy are particularly painful in the groin

area Wide excision has high recurrence rates of up to

44%.3 Considerable morbidity is associated with

radical vulvectomies, scrotectomies, orchiectomies,

and penectomies Recently, topical imiquimod has

been reported to be a useful treatment modality.14,15

Mohs micrographic excision does have theoretical

advantages for this type of tumor, which has clinically

indistinct margins, subclinical extension, high local

recurrence rates, and potential for metastasis Tissue

preservation is also important because the tumor often

encroaches on vital structures.16,17 Preoperative

topi-cal 5-fluorouracil has been used to delineate the extent

of the disease.18

Methods

To formulate treatment recommendations for this rare

disease, we conducted a retrospective review of

out-come for 95 patients after surgical treatment of

extramammary Paget’s disease during a 25-year period

between 1976 and 2001 at the Mayo Clinic (Roche-ster, Minnesota, and Scottsdale, Arizona) The study was approved by the Mayo Foundation Institutional Review Board The factors studied included age, gender, tumor site, whether tumor was primary or recurrent, and associated neoplasms We examined outcome after surgical treatment and followed a subgroup treated with Mohs micrographic excision

Figure 1 Patient with extensive extramammary Paget’s disease over

the left groin.

(a)

(b)

Figure 2 Pagetoid cells in the epidermis (a) Low power (hematox-ylin and eosin; 10) (b) Higher power (hematox(hematox-ylin and eosin; 100).

We noted preoperative strategies to delineate tumor

extent and methods of histologic margin assessment

Number of layers for clearance, postoperative defect

size, and method of repair were also noted The data

were evaluated to formulate treatment

recommenda-tions for this rare disease

Results

Ninety-five patients (45 men and 50 women) with

biopsy-proved disease were studied The mean age was

70.4 years for the men and 69.8 years for the women

(overall range, 53 to 87) Contiguous carcinoma was

found in 19 of the 95 patients (20%) The most

common primary disease sites were the vulva, anal and

perianal region, inguinal fold, scrotum, penis, and

axilla The patient with axillary disease also had

simultaneous disease in the perineum Eighty-six

patients had primary disease, and nine had recurrent

disease 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 noted

frequently, and some patients received CO2 laser or

radiation 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 in

four patients, and carcinoembryonic antigen also was

used in two of these four patients

Preoperative scouting biopsies were performed in

five patients Photodynamic diagnosis was used in two

patients (Figure 4) Photodynamic therapy with

d-aminolevulinic acid (Levulan Kerastick) and Wood’s

light 16 to 18 hours later also was attempted in one patient

The length of follow-up was determined by clinical examinations or biopsy specimens recorded in the patients’ medical record At follow-up (mean of 24 months), local disease had recurred in one Mohs patient (8%) A second patient died of metastatic adenocarcinoma of an unknown primary cause, which raises the question of whether sentinel lymph node biopsy should be performed in advanced cases Of those patients treated with Mohs surgery, one patient was allowed to heal by second intention, and eight had defects that were closed primarily, which emphasizes that extensive laxity in the scrotum often allows primary repair despite large defects Two patients underwent repair with a flap, and one patient had a combined flap full-thickness and split-thickness graft Five patients required more than two layers Two

Table 1 Twelve Cases of Extramammary Paget’s Disease Treated With Mohs

adenocarcinoma

S 5 preoperative scouting biopsy; 1 5 subsequent day(s) of Mohs.

n Number of layers required for tumor removal on subsequent days of Mohs.

Figure 3 Positive staining of extramammary Paget’s disease with intraoperative cytokeratin 7 at time of Mohs.

(c) (e)

(d)

Figure 4 (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 is helpful in guiding the first Mohs layer (d) (e) Primary closure after clearance.

patients had Mohs lasting more than 1 day This

reinforces the importance of preoperative tumor

visualization

Discussion

The initial diagnosis of extramammary Paget’s disease

is often delayed, and early biopsy should be considered

in patients with tinea cruris or erythrasma who are

unresponsive to appropriate therapy All patients

should have a thorough work-up to exclude

under-lying gastrointestinal, genitourinary, or internal

malig-nancy Immunophenotypes other than cytokeratin 71/

cytokeratin 20– in Paget’s cells suggest underlying

regional internal malignancy

Preoperative scouting biopsies may be helpful in

planning Mohs operations for patients with this

disease Shave biopsies are appropriate at the

periph-ery of the tumor, but punch biopsy may be more

helpful at its center to evaluate the degree of adnexal

and deeper dermal involvement In advanced cases

with dermal involvement, sentinel lymph node biopsy

may be a consideration Photodynamic diagnosis using

topical d-aminolevulinic acid and Wood’s light 16 to

18 hours later also may help delineate the extent of

disease, as may preoperative topical 5-fluorouracil

Cytokeratin 7 is the immunostain of choice for

intraoperative immunostaining It is important to have

a histotechnician who is experienced with the

proces-sing of large tissue sections Histologic discrimination

between eccrine coil and dermal Paget’s disease may

also be difficult on frozen sections, and a debulking

layer for permanent sections with Mohs for the

peripheral margin may be a useful option

Treating patients with this type of tumor requires a

multidisciplinary approach that involves a colorectal

surgeon and a urologist in the work-up, because their

expertise may be required in following any urethral

and anal extensions of the disease and in repairing

defects in these areas Preoperative 5-fluorouracil or

photodynamic diagnosis may be used to assess

whether extension to these structures has occurred

Photodynamic diagnosis may also be considered in

following these patients because recurrences often lack

symptoms and are not visible clinically A biopsy

should be performed if in doubt

We found that Mohs micrographic surgery

com-pared favorably with wide excision and had a local

recurrence rate of 8% (at mean follow-up of 24

months) versus 22% for patients who underwent wide

excision (at mean follow-up of 65 months) Longer

follow-up of these patients and a prospective study of

a larger series of patients may provide additional

support for Mohs as an excellent treatment for this disease

Acknowledgments Dr O’Connor is the recipient of the 2001 Theodore Tromovitch award for this article, which was presented at the Mohs Meeting, Dallas, Texas, October

2001 As a recipient of this award, Dr O’Connor submitted his article to Dermatologic Surgery for publication.

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