Extramammary Paget’s disease a review of the literature.pdf

Review
Extramammary Paget’s disease: a review of the literature
Robert M. Simonds1
, MD, Robert J. Segal2
, MD, and Amit Sharma3
, MD
1
Department of Dermatology, Cleveland
Clinic Foundation, Cleveland, OH, USA,
2
Division of Dermatology, University of
Arizona, Tucson, AZ, USA, and 3
Kaiser
Permanente, Hillsboro, OR, USA
Correspondence
Robert Simonds, MD
Department of Dermatology, Cleveland
Clinic Foundation
9500 Euclid Ave
Cleveland, OH 44195
USA
E-mail: simondr@ccf.org
Conflicts of interest: The authors declare no
conflicts of interest.
doi: 10.1111/ijd.14328
Abstract
Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy. The disease
typically affects older individuals aged 60–80 years and is seen most frequently in
postmenopausal Caucasian women and Asian men. EMPD exhibits a predilection for the
genital and perianal regions and may be associated with an underlying carcinoma in
adjacent organs. EMPD presents a challenge in both diagnosis and management. Often
treated empirically as various dermatitides, the correct diagnosis is frequently delayed by
many years. Following diagnosis, an extensive search for an associated malignancy should
be initiated. If invasive disease is present on biopsy, a sentinel lymph node biopsy may
guide further treatment. Mohs micrographic surgery appears to be superior to wide local
excision when considering tissue sparing ability and disease recurrence. Nonsurgical
interventions have also been investigated with varied results. Regardless of treatment
method, long-term follow-up is recommended to monitor for local disease recurrence,
development of internal malignancy, regional lymphadenopathy, or distant metastasis.
Introduction
Extramammary Paget’s disease (EMPD) is an uncommon
intraepithelial adenocarcinoma. In 1889, Radcliffe Crocker
described the first case of EMPD affecting the penis and scro-
tum found to be associated with an underlying bladder cancer.
Due to its rarity, the exact incidence of EMPD is unknown.1
EMPD typically affects older individuals aged 60–80 years, with
the highest incidence at 65 years of age.2,3
The most commonly
affected groups are postmenopausal Caucasian women and
Asian men, with a female preponderance of 3:1.1,3,4
Familial
occurrence is quite rare, with only seven reported cases found
within the Japanese and British literature combined.5
Clinical Manifestations
While the origin of EMPD is still in debate, EMPD largely affects
those areas with a high apocrine gland concentration including
the genital skin, axillae, and anus.1,3–5
The vulva is the most
commonly affected region and accounts for nearly 65% of all
cases of EMPD. Despite the high frequency of vulvar involve-
ment, EMPD only accounts for roughly 1–2% of all vulvar malig-
nancies. Four to 17 percent of vulvar EMPD is associated with
underlying cutaneous adnexal carcinomas, with 11–20% of
cases being related to carcinoma of the vagina, colon, rectum,
or urogynecologic structures.5,6
Perianal involvement comprises 20% of EMPD cases in both
genders and has the highest incidence of related underlying
malignancy.7
Reported rates of underlying malignancy range
from 33% to 86% and are typically rectal or tubo-ovarian cancers.8,9
Involvement of the male genitalia comprises 14% of EMPD
cases, with 11% of cases associated with neoplasms of the
prostate, testes, and bladder.5
Notwithstanding the perineal and
genital predominance, EMPD has been reported to occur in
areas either containing much smaller concentrations or com-
pletely devoid of apocrine glands such as the abdomen, eyelid,
and cheek.5,10,11
Such cases are extremely rare and have been
termed “ectopic EMPD.” Theories as to how this occurs are
based on the belief that Paget cells are derived from pluripotent
germinative cells capable of differentiating into either apocrine
or eccrine glands (depending on stimulus).10,11
Primary lesions of EMPD mimic various dermatitides such
as eczema, intertrigo, psoriasis, or fungal infections. Typically
presenting as a well-demarcated, erythematous plaque,
lesions may also demonstrate secondary changes including
scale, ulceration, or even bleeding3–5
(Figs. 1 and 2). In
Asian patients, clinicians must be aware that a hypopigmen-
ted macule or patch may represent a primary or recurrent
lesion of EMPD.12
EMPD tends to display multifocal growth
with subclinical extension into seemingly normal-appearing
skin, thus creating issues when attempting to obtain clear
surgical margins.
Occasionally, EMPD may present with concurrent lesions
involving the anogenital and axillary regions (known as double,
triple, or synchronous EMPD).13
The exact mechanism as to
why this occurs is unknown. Although multiple EMPD is quite
ª 2018 The International Society of Dermatology International Journal of Dermatology 2018
1

rare, a thorough physical examination of these regions is extre-
mely important when one encounters EMPD.
A unique presentation of genital EMPD is known as “under-
pants pattern erythema.” This clinical feature begins in the groin
and spreads to areas covered by underwear. Thought to be due
to lymphatic invasion, it heralds a poor prognosis as it is related
to distant metastasis. Of the six cases described by Murata
et al., all patients demonstrating underpants pattern erythema
died of metastases to distant organs.14
The lesions of EMPD may be entirely asymptomatic or may
produce variable degrees of pruritus, burning, or tender-
ness.1,3,4
Due to the nonspecific nature of symptoms, EMPD is
generally not suspected early in its course and is empirically
treated with corticosteroids or antifungals. Not surprisingly,
EMPD is unresponsive to these conventional therapies.
When symptoms or lesions persist and empiric therapy fails,
clinicians should be alerted to consider an alternative diagnosis
and pursue further studies. Ultimately, a skin biopsy is
necessary to make the diagnosis of EMPD. Unfortunately, the
correct diagnosis is usually delayed by an average of 2 years,
with reports of delay extending up to 10 years or more.3,4,15
Pathogenesis
Despite immunohistochemical staining of Paget cells demon-
strating the epithelial/glandular nature, the exact origin of EMPD
is not fully understood. It is generally agreed that two forms of
the disease exist, each with a distinct pathogenesis.3–5
Primary EMPD is an intraepithelial neoplasm that appears to
originate within the epidermis or apocrine glands. This form is
not associated with an underlying malignancy. Primary EMPD is
considered in situ (confined to the epidermis), but it harbors the
potential to become invasive and/or metastatic disease over
time. The precursor cell may be a pluripotent epidermal or
adnexal cell. A popular theory proposes Toker cells to be the
precursor to EMPD. Toker cells are intraepithelial cells with
clear to pale-staining cytoplasm, and they have been reported
to be associated with mammary-like glands located within the
vulva.16,17
Secondary EMPD, the less common form of the disease, is
thought to develop from the epidermotropic spread of malignant
cells from an underlying internal neoplasm. The underlying car-
cinomas are typically within dermal adnexal glands or organs in
the near vicinity of the cutaneous lesion.3–5,18
Histologic Evaluation
Histopathological examination is a vital tool in the diagnosis of
EMPD. Biopsy analysis should include routine hematoxylin and
eosin staining as well as immunohistochemical stains. The char-
acteristic Paget cells are large, round, atypical intraepithelial
cells containing pale-staining vacuolated cytoplasm and promi-
nent nuclei.1,4,19,20
The large cytoplasmic vacuoles are due to
abundant mucin, which is easily recognized by histochemical
stains such as PAS/alcian blue.20
Specific immunohistochemical stains are utilized to identify
Paget cells, differentiate between primary and secondary forms
of EMPD, and also to exclude other diagnoses on the differen-
tial such as Langerhans cell histiocytosis, squamous cell carci-
noma in situ (Bowen’s disease), amelanotic melanoma, and
mycosis fungoides.3,4,20
Cytokeratin stains such as CK7 and CK20 may be utilized to
help categorize EMPD and predict whether or not an underlying
malignancy may be present. CK7 is a sensitive (although non-
specific) marker of EMPD. CK20 tends to be present in many
carcinomas of the gastrointestinal and urothelial tracts.21
Thus,
primary EMPD generally stains CK7+
and CK20 , while sec-
ondary EMPD usually stains CK7+
and CK20+
. Gross cystic dis-
ease fluid protein (GCDFP-15) is strongly expressed in cases of
EMPD without underlying malignancy.21
Carcinoembryonic anti-
gen (CEA) is reported to be immunoreactive in 67% of urothelial
Figure 1 Large erythematous eroded plaque located on the
posterior right scrotum of a 79-year-old Caucasian male
Figure 2 Asymptomatic pink plaque with slight scale present in the
right axilla of a 77-year-old male
International Journal of Dermatology 2018 ª 2018 The International Society of Dermatology
Review Review of extramammary Paget’s disease Simonds, Segal, and Sharma
2

carcinomas and in over 90% of colorectal adenocarcinomas. As
most cases of primary vulvar EMPD are immunoreactive for
CEA, immunohistochemical staining for CEA offers little benefit
when differentiating primary from secondary vulvar EMPD.22
Other reliable markers for EMPD include EMA and PAS.1,3,19,20
Genetic and Protein Expression Profiles
The genetic characteristics of EMPD lesions have become
important prognostic factors.23
HER2, Ki-67, cyclin D1, and
MUC5AC are among markers under recent investigation. The
oncoprotein, HER2, appears to be one of the most studied
genetic alterations in EMPD, likely due to its therapeutic poten-
tial and relationship with mammary Paget disease (MPD).
HER2 is overexpressed in 70–100% of MPD cases; however,
reported rates of HER2 overexpression within EMPD varies.24
In a recent study, HER2 overexpression and amplification of
ERBB2 (the gene encoding HER2) were seen more frequently
in cases of invasive disease. This profile also correlated with a
larger number of lymph node metastases.25
Aoyagi et al. observed Ki-67 and cyclin D1 to be expressed
at significantly higher levels within invasive lesions when com-
pared to in situ lesions. Additionally, lesions demonstrating
simultaneous expression of both Ki-67 and cyclin D1 were more
likely to be invasive than those expressing Ki-67 or cyclin D1
alone.26
MUC5AC is another gene frequently expressed within inva-
sive and metastatic lesions.27
MicroRNAs (miRNAs) are small
noncoding RNAs that contribute to the development of cancer.
In a recent study, miR-375, miR-31, and miR-31* were found to
be upregulated in Paget cells when compared with cells from
normal epidermis and apocrine glands. Thus, miR-375, miR-31,
and miR-31* may contribute to the development of EMPD and
potentially serve as biomarkers of EMPD.28
Screening for Malignancy
Once a diagnosis of EMPD is established, an extensive investi-
gation for underlying malignancy should be performed as 30%
or more cases may be complicated by an associated malig-
nancy4,29
(Table 1). Depending on the anatomic location
involved, certain underlying malignancies may appear more fre-
quently. For example, perianal lesions are more commonly
associated with anal or colorectal carcinomas.8,9,21
Accordingly,
depending on the gender of the patient, appropriate studies to
be considered include mammography, pap smear, pelvic ultra-
sonography, cystoscopy, colonoscopy, and computed tomogra-
phy of the abdomen and pelvis.3–5
Preoperative Examination
Depth of invasion and extracutaneous involvement (lymphovas-
cular structures or distant metastases) have been shown to
predict poor prognosis in EMPD.23
Hence, detection of micro-
scopic metastases via sentinel lymph node biopsy (SLNB) has
been studied to determine if nodal status influenced survival.
Hatta et al. reviewed 13 cases of primary EMPD who also
underwent SLNB. They found three of four patients with dermal
invasion also had lymph node metastases on SLNB. Their
results correlated well with prognosis, as nine cases with nega-
tive SLNB were disease free during the follow-up period (3–
50 months) and three of four cases of positive SLNB also had
visceral or distant metastases.30
Recently, Ogata et al. demonstrated similar findings in their
retrospective review of 59 cases of primary EMPD who
underwent SLNB. In their study, nodal status influenced sur-
vival, as 5-year survival rates were 100% with negative SLNB
and only 24% with nodal involvement. Interestingly, they also
found the number of involved nodes to have prognostic impli-
cations. The 5-year survival was 100% for those with two or
less metastatic nodes and 0% when three or more nodes
were involved.31
On the other hand, Fujisawa et al. performed a retrospective
review of 151 cases of invasive EMPD. Of these, 107 cases with-
out clinical lymphadenopathy underwent SLNB, with 16 cases
demonstrating nodal involvement. Again, depth of invasion was
an important predictor of positive SLNB. However, in their study,
estimated survival between those with positive and negative
SLNB was remarkably similar. They thought the early detection of
lymph node involvement and subsequent total lymph node dis-
section may have improved survival in those cases.32
Most authors agree that given the relative safety of the pro-
cedure, SLNB should be considered in cases where invasive
disease is suspected.23,30–32
In small studies, positron emission tomography-computed
tomography (PET-CT) has proven useful for determining extent
Table 1 Reported cases of concurrent malignancy in EMPD
Study
Number of
EMPD cases
reviewed
Percent of patients
with concurrent
malignancy
Chanda et al.,29
1985 197 12%
Coldiron et al.,15
1991 48 6%
Shieh et al.,54
2002 5 0%
Luk et al.,57
2003 6 33%
Pierie et al.,33
2003 33 42%
Hendi et al.,35
2004 25 8%
Siesling et al.,2
2007 223 32.7%
Zhu et al.,38
2007 38 0%
Hatta et al.,30
2008 76 0%
Minicozzi et al.,7
2010 6 17%
Bae et al.,41
2013 86 9.3%
Kang et al.,19
2015 246 8.1%
Liau et al.,49
2016 6 0%
Kim et al.,42
2017 207 24%
Long et al.,40
2017 154 18%
Simonds, Segal, and Sharma Review of extramammary Paget’s disease Review 3

of disease and revealing distant metastasis. However, similar to
melanoma staging, the sensitivity of PET-CT to detect micro-
scopic metastases is dependent upon tumor size.3,23
Surgical Treatment
Wide local excision (WLE) has long been regarded as the gold
standard for management of EMPD. However, due to the multi-
focal nature and discontinuous subclinical extension of Paget
cells, disappointing recurrence rates have been reported to
range from 30% to 61%.15,33,34
Accordingly, efforts have been
made to improve the efficacy of WLE and decrease the number
of disfiguring procedures required to manage EMPD.
A standard surgical margin of healthy-appearing skin has yet
to be agreed upon, with recommendations ranging anywhere
from 1 to 5 cm.35–37
As the majority of EMPD cases tend to
involve the genitals, obtaining clear margins while resecting the
least amount of tissue is an obvious goal.36
Frozen section analysis has been employed as a means to
offer better margin control, although opinions vary on the utility
of such evaluation.37–39
With frozen section guided WLE, Zhu
et al. achieved an acceptable recurrence rate of 16% in peno-
scrotal EMPD.38
However, Black et al. reported no correlation
between disease recurrence and margin status. In their series
of 28 patients with vulvar EMPD, recurrence occurred in 70% of
those with positive margins and 38% of those with negative
margins.39
The ultimate margin control comes in the form of Mohs
micrographic surgery (MMS). Due to the processing technique,
conventional frozen section analysis only observes 0.1–1.0% of
the actual surgical margin, whereas Mohs surgery offers the
ability to observe nearly 100% of the margin.3,15,35,40
MMS has
become the gold standard for the removal of certain skin can-
cers. However, due to the rarity of EMPD, the efficacy of MMS
in the management of EMPD is still under investigation.41–43
In 1991, Coldiron reported six cases of genital EMPD treated
with MMS.15
In all cases, there was extension well beyond the
clinical margins. They noted two cases recurred during follow-
up. In their report, they also reviewed the results of a survey
sent to all 202 members of the Mohs College of Micrographic
Surgery. Based on survey responses, they identified 48 cases
of EMPD treated with MMS. Of these, 11 of 48 recurred, giving
a recurrence rate of 23%, which was lower than the 33% recur-
rence rate for MMS in the literature at the time.
Similar studies performed by O’Connor,44
Hendi,35
and Bae41
also sought to determine the efficacy of MMS compared to WLE
in management of EMPD. O’Connor et al. performed a retrospec-
tive review of 95 cases treated between 1976 and 2001. Of these,
12 underwent MMS with only 1 of 12 (8%) recurring at a mean fol-
low-up of 24 months. Of those treated with WLE, 18 of 83 (22%)
recurred at a mean follow-up of 65 months.
In 2004, Hendi et al. reviewed their experience with 27 cases
of EMPD treated with MMS.35
Of these, 19 were primary tumors
and eight were recurrent lesions previously treated by WLE. At
a mean follow-up of 59.2 months, three of 19 (16%) in the pri-
mary group recurred. Of those who previously underwent WLE,
four of eight (50%) recurred following MMS, yielding a compos-
ite recurrence of seven of 27 (26%). All seven recurrent lesions
were retreated with MMS, and at a mean follow-up of
76.2 months, none had recurred, suggesting the utility of MMS
as salvage treatment for recurrent lesions. Interestingly, in their
analysis, they determined removing a 5 cm margin of normal-
appearing skin was required to obtain microscopically clear mar-
gins in 97% of cases, whereas a 2 cm margin would have only
cleared 59%. Thus, the authors recommended 5 cm margins
for cases where MMS cannot be used.
More recently, Bae et al. performed a pooled analysis of
eight studies comparing recurrence rates between MMS and
WLE.41
Eleven of 90 (12.2%) treated with MMS recurred, with
an estimated 5-year tumor-free rate of nearly 84%. In 2017,
Kim et al. reported two of 19 (11%) recurrence with MMS com-
pared to 16 of 45 (36%) recurrence with WLE.42
When directly
comparing MMS to WLE, there was an improvement of nearly
40% in estimated 5-year recurrence-free survival rates with a
hazard ratio of 0.23. While recurrence can still be an issue, from
the results of these recent studies, MMS appears to be the
superior form of surgical treatment for EMPD.
Scouting biopsies have been utilized to improve the effi-
cacy of MMS as well as WLE.15,44–46
Such biopsies are
taken anywhere from 1 to 5 cm lateral from clinically involved
margins (Fig. 3). Appert et al. performed scouting biopsies on
five patients prior to MMS with biopsies revealing subclinical
extension in four of the five cases.45
Proposed benefits
include: increased preoperative knowledge, improved effi-
ciency with fewer MMS stages, decreased morbidity, better
planning for reconstruction, and improved patient counseling
regarding expectations.
Despite the proposed benefits, a recent retrospective study
performed by Kaku-Ito et al. suggests scouting biopsies may
not always be necessary.46
In cases of well-defined EMPD, of
810 biopsies performed, only 13 (1.6%) were positive for Paget
cells. For EMPD with ill-defined borders, of 165 biopsies, only
eight (4.6%) demonstrated Paget cells. Interestingly, when com-
paring margin positivity between patients who underwent scout-
ing biopsies prior to surgery and those without, there was no
significant difference in the rate of positivity. The authors con-
cluded scouting biopsies had no benefit with well-defined EMPD
or when surgical margins of 2 cm were obtainable. However,
for cases of ill-defined EMPD, scouting biopsies may be of use
when surgical margins must be less than 2 cm.
Alternative methods to determine the actual margin prior to
surgery include topical 5-fluorouracil and photodynamic therapy
with d-aminolevulinic acid followed by Wood’s light.15,44
Another surgical issue to consider is the necessity of lymph
node dissection (LND) in cases where SLNB is positive. Tsut-
sumida et al. sought to determine the indications for LND in
4

EMPD.47
They identified 34 patients with EMPD and classified
them into four groups based on pathological tumor invasion:
Carcinoma in situ (CIS), microinvasion to papillary dermis
(MIPD), invasion to reticular dermis (IRD), and invasion to sub-
cutaneous tissue (IST). In patients with CIS or MIPD, no LND
was performed, and subsequently no patients died from the dis-
ease. Of the six patients with IRD, four underwent LND. Three
of the six patients showed lymph node metastasis and ulti-
mately died. Of the six patients with IST, all patients underwent
LND. All six patients had lymph node metastasis and died from
the disease. As described, their results once again demon-
strated how tumor invasion level correlates with disease prog-
nosis. Based on their results, the authors recommended
therapeutic LND when lymph node biopsy is positive. LND was
deemed unnecessary in cases of CIS or MIPD without clinical
or pathologic lymph node metastasis. However, in cases of IRD
or IST without clinical or pathologic lymph node metastasis,
elective LND was strongly recommended.47
While the previous study set forth indications for LND in
EMPD, it failed to demonstrate whether or not LND offered any
survival benefits. In a retrospective review, Fanning et al.
reported 12 patients with invasive lesions classified as either
“microinvasive” or “deeply invasive”. None of the 12 patients
underwent LND, and ultimately none died of the disease.48
As
EMPD is a rare entity, more evidence is required to determine if
LND offers any increase in survival.
Nonsurgical Interventions
For patients unwilling to undergo surgical treatment, or who are
otherwise not surgical candidates, alternative treatment modali-
ties such as topical chemotherapy, photodynamic therapy, and
radiation therapy may be beneficial.
Topical imiquimod has shown promise as a viable alternative
to surgery. By stimulating the production of multiple cytokines,
imiquimod activates the immune system to create an antitumor
effect.49
Multiple studies have reported topical imiquimod 5%
cream to be effective for EMPD, with response rates ranging
from 52% to 100%, and recurrence rates up to 20%.49–52
In a
recent prospective study by Sawada et al., the response rate
with imiquimod was 100%, with five of nine patients achieving
complete response (complete clinical or histopathological remis-
sion). Three of five patients who achieved complete response
ultimately recurred, demonstrating the importance of long-term
observation even in cases where complete response is con-
firmed histopathologically.52
Despite the benefits of imiquimod,
unpleasant local and systemic side effects such as erythema,
erosion, fever, and flu-like symptoms occur in more than 50%.53
As the favorable results of imiquimod have only been seen in
relatively small cohorts, further trials are needed to confirm effi-
cacy and establish treatment guidelines.
Photodynamic therapy (PDT) is a noninvasive treatment uti-
lizing photoreactive drugs, such as d-aminolevulinic acid, that
are selectively taken up by tumor cells.51,54,55
The involved area
is then exposed to the appropriate wavelength of light, creating
toxic free radicals that destroy tumor cells in the process.
Response rates range from 14-50% and have recurrence rates
of 38–56%.51
The major adverse reaction reported is burning
and pain.
The role of radiotherapy (RT) in management of EMPD is
somewhat poorly understood as most literature is composed of
case reports or small case series. Initial reports of RT demon-
strated recurrence rates up to 80%.56
However, more recent
reports for vulvar EMPD exhibit recurrence rates from 0% to
35%.51
Wet desquamation and skin atrophy are common com-
plications of RT.51,56,57
Similar to topical therapy and PDT,
there are currently no established guidelines on radiation
dosages and frequency of treatment.57
In the case of metastatic EMPD, no clear chemotherapy regi-
mens have been established. Multiple regimens have been
attempted, each with varying levels of success. In the Japanese
literature, first-line agents appear to include taxane monotherapy
or taxane-based chemotherapy.58
Kato et al. recently reported
favorable response in two patients with TS-1 monotherapy follow-
ing docetaxel resistance.59
As nearly 60% of EMPD demon-
strates HER2 gene amplification, trastuzumab and paclitaxel
have yielded favorable responses in many individual reports.60
Recent investigations into the pathogenesis of metastatic EMPD
have identified multiple signaling pathways that provide potential
therapeutic targets for novel drug development in the future.61
Figure 3 Large pink plaque located in the left groin of a 70-year-
old male. Black markings signify planned sites for scouting biopsies
prior to surgical treatment

Follow-Up
Disease recurrence remains a concern regardless of treatment
method as EMPD may recur up to 15 years following initial diag-
nosis4,5
(Fig. 4). Accordingly, long-term surveillance is recom-
mended to monitor for local recurrence, development of internal
malignancy, regional lymphadenopathy, and distant metastasis.
In a study based on the SEER Program data, Karam et al.
observed that patients with invasive EMPD have greater than
50% increased risk of developing secondary malignancies fol-
lowing their original diagnosis. The nature of secondary malig-
nancy reflected the site of the original lesion. Contrary to
previously reported data, they observed no significant increased
risk for malignancy at distant sites (bladder, breast, etc.). Their
results underscore the importance of close clinical follow-up
tailored by the site of the original lesion.62
In addition to careful physical examination, serum levels of
tumor markers may provide a way to identify disease progres-
sion and monitor treatment efficacy. CEA is a known tumor
marker for many adenocarcinomas such as colon cancer. As
EMPD exhibits similarities with adenocarcinomas, the utility of
serum CEA levels in cases of metastatic EMPD has been
investigated. In a series of 76 patients with EMPD, Hatta et al.
measured CEA levels in 60 patients, with only 10 patients
showing elevated values. All patients with elevated CEA levels
were found to have systemic EMPD metastases. While CEA
levels do not appear to serve as a marker for EMPD confined
to the skin, CEA levels may be an important indicator of sys-
temic metastasis or response to treatment.34
Another tumor marker under recent investigation is cytoker-
atin 19 fragment 21-1 (CYFRA 21-1). Kato et al. assessed
serum levels of CYFRA 21-1 and CEA in 13 patients with
Figure 4 General approach to diagnosis and management of EMPD. EMPD, extramammary Paget’s Disease
6

EMPD prior to treatment. At the time of diagnosis, four patients
had lymph node involvement, but none had distant metastases.
Serum CEA levels were normal in all 13 patients, but 6 of 13
(46.2%) demonstrated elevated CYFRA 21-1. During post-treat-
ment follow-up, measured levels of CYFRA 21-1 were reduced
in all six patients. Four of the six patients ultimately developed
recurrence and metastatic disease. In these patients, CYFRA
21-1 was significantly re-elevated at recurrence, whereas serum
CEA was only elevated in one patient with liver metastasis.
Interestingly, during the same follow-up period, none of the
seven patients with normal levels of CYFRA 21-1 developed
recurrence. The results of their study suggested CYFRA 21-1 is
useful in the monitoring of disease relapse and response to
treatment.63
Conclusion
Extramammary Paget’s disease is a rare cutaneous malig-
nancy with predilection for the genital region and may be
associated with an underlying carcinoma in adjacent organs.
EMPD presents a challenge in both diagnosis and manage-
ment. Often treated empirically as various dermatitides, the
correct diagnosis is frequently delayed by years. Following
diagnosis, an extensive search for an associated malignancy
should be initiated. Mohs micrographic surgery appears to be
superior to wide local excision when considering tissue spar-
ing ability and disease recurrence. Nonsurgical interventions
have also been investigated with varied results. Regardless of
treatment method, long-term follow-up is recommended to
monitor for local disease recurrence, development of
internal malignancy, regional lymphadenopathy, or distant
metastasis.
Questions (answers provided after
references)
1 Extramammary Paget’s disease (EMPD) tends to occur most
often in which patient population?
A- Premenopausal Asian women
B- Asian males less than 50 years of age
C- Postmenopausal Caucasian women
D- Caucasian males over 60 years of age
2 What anatomic location is most frequently affected by
EMPD?
A- Abdomen
B- Axilla
C- Scrotum
D- Vulva
3 Which form of EMPD appears to have the highest rate of
associated malignancy?
A- Vulvar
B- Perianal
C- Ectopic
D- Axillary
4 EMPD can mimic which of the following common disorders?
A- Psoriasis
B- Intertrigo
C- Eczema
D- Fungal Infections
E- All of the above
5 Overexpression of which of the following is associated with
invasive disease?
A- HER2/ERBB
B- Ki-67 and cyclin D1
C- MUC5AC
D- All of the above
6 Which immunohistochemistry profile is most typical of primary
EMPD?
A- CK7+
and CK20
B- CK7+
and S100+
C- CK20+
and CD1a
D- CK7 and Melan-A+
7 When present, which immunohistochemical marker suggests
the lack of an underlying malignancy?
A- CK20
B- MUC1
C- GCDFP-15
D- PAS
8 In order to exclude associated malignancy, appropriate stud-
ies following diagnosis include?
A- Colonoscopy
B- Mammography
C- Abdominal CT
D- All of the above
9 What is the most important prognostic indicator in EMPD?
A- Anatomic location
B- Depth of invasion
C- Bleeding
D- Size of initial lesion
10 Which of the following contribute to the high rates of recur-
rence seen with EMPD?
A- Ill-defined clinical borders
B- Subclinical extension of Paget cells
C- Multifocal nature of Paget cells
D- All of the above
References
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