KEY POINTS:
- EMPD represents an intraepithelial carcinoma whose diagnosis is often
delayed and it is based on histopathological and Immunohistochemistry.
Once diagnosis is made, investigation for an underlying carcinoma has
to be done.
- Extramammary Paget’s treatment is a difficult issue due to intolerance
and recurrence; topical treatments can be an alternative and imiquimod
and photodynamic therapy can be used safely and effectively in
combination.
Extramammary Paget’s disease (EMPD) represents an intraepithelial
carcinoma which occurs in apocrine gland-bearing
skin1. Surgery is the treatment of choice but
non-invasive options such as radiotherapy or topical chemotherapy are
alternatives to consider in patients that are medically unfit for
surgery or recur2.
An 83-year old woman presented with a 2-year history of pruritus on her
vulvar area. She had consulted several physicians who had prescribed
antifungal and corticosteroid ointments without improvement. The lesion
had been slowly growing and had started to be painful and to present
small erosions on its surface. Physical examination revealed
erythematous and scaly plaques with superficial small erosions affecting
the skin of her right labia majora and gluteus (Fig.1).
Due to failure to treatment, punch biopsy was performed (Fig.2). An
epidermal infiltration by large atypical, eosinophilic cells, with wide
cytoplasm and prominent marginal nuclei, scattered throughout all layers
of epidermis was found. This proliferation was not found deeper in
dermis nor subcutaneous tissue. Immunohistochemistry showed positivity
for cytokeratin 7 (CK7) and CK20 stain was negative. These
histopathological findings were consistent with Paget cells, and,
suggestive of primary EMPD. Nevertheless, body computed tomography,
gastroscopy, colonoscopy, gynaecologic ultrasonography and cervical
cytology were performed without evidence of malignancy.
Surgery was offered but patient preferred a conservative option.
Imiquimod 5% cream was started: 3 applications per week, once at night,
during 16 weeks. Due to multifocal lesions, treatment was performed
first in the vulva and, secondly, in the gluteus. Complete response was
obtained clinically and histopathologically.
Recurrence was experienced six months after and imiquimod was restarted.
This second application was not tolerated and photodynamic therapy (PDT)
using methyl aminolevulinate was initiated. Complete remission was
achieved after four sessions of PDT (red light, 630nm, 37 J/cm2, 7
minutes; two sessions per area, one session per week). After twelve
months, imiquimod was successfully reused with control of disease after
second recurrence.
Extramammary Paget’s disease (EMPD) was first described in 1889 by
Croker as a cutaneous carcinoma located in the genital area of a 60
year-old man that presented with clinical and histological features
similar to those found in Mammary Paget’s disease2,
defined by James Paget in 1874. Although its pathogenesis remains
controversial, in primary disease, it represents an intraepithelial
carcinoma most likely derived from the intraepithelial sweat
duct2.
Extramammary Paget’s disease (EMPD) commonly involves the vulva but can
also be found in perianal skin, scrotum, penis and axilla. Pruritus is
the most common symptom; burning, irritation, pain, tenderness, bleeding
and swelling can also be present3. Patients develop
well-defined erythematous and scaly plaques that can associate crust,
liquenification, erosions and ulceration. Its characteristic
“cake-icing” appearance was first described by
Dubreuilh4, due to the presence of white islands and
bridges of hyperkeratotic epithelium upon erythema.
It can be easily misdiagnosed as a benign dermatitis and be mistaken for
eczema, psoriasis, fungal infection and seborrheic
dermatitis2. That is the reason why diagnosis and
definitive treatment are often delayed. Skin biopsies should be
performed in all patients with eczematous or infectious lesions that
have failed to respond to standart topical
treatment3.If lymphadenopathies or palpable nodules
are present, they raise suspicion for invasive
disease2.
EMPD’s diagnosis rests on histological criteria. Immunohistochemistry
studies are mandatory to make the diagnosis and to exclude anogenital
intraepithelial neoplasm and malignant melanoma5. EMPD
can also represent an epidermotropic metastasis from a distant malignant
neoplasm (secondary EMPD); this technique also contributes to
differentiate between primary and secondary EMPD6.
Paget’s cell stain for markers of apocrine and eccrine lineage such as
low molecular weight cytokeratins (such as CK7), gross cystic disease
fluid protein (GCDFP-15), periodic acid-Schiff (PAS) and
carcinoembryonic antigen (CEA)5-6 and, therefore, this
technique helps to identify the likely cell of origin as primary and
secondary disease show different immunophenotypes7.
Cytokeratin 20 (CK20) is an epithelial marker with restricted expression
compared to CK76.
Primary EMPD stains for CK7 and GCDFP-15, being CK20 negative; secondary
EMPD is CK20 positive and GCDFP-15 negative7. Our case
showed an Immunohistochemistry profile of primary disease (CK7 positive;
CK 20 negative) (Fig 2). After the diagnosis of EMPD is made, especially
with a secondary disease profile, investigation for an underlying
carcinoma has to be made. Gastrointestinal and genitourinary neoplasm
can be found in up to 20% of EMPD patients2-3.
Although generally accepted as the standard treatment, all surgical
modalities are associated with high local recurrence
rates8. Margins are difficult to assess even in frozen
sections and wide local excision have been associated with important
recurrences rates as well and conservative techniques are been performed
nowadays. Radiotherapy can be an alternative as primary treatment but,
it should be only consider in patients medically unfit for surgery or
after recurrence9.
Topical chemotherapy agents9-10, such as
5-fluorouracil, imiquimod and bleomycin and photodynamic therapy, have
been used to treat EMPD. They can be useful as cytoreduction prior to
surgery, early disease recurrence and as primary treatment for those
where surgery is not an option. All topical modalities can produce
severe local reactions and a subsequent lack of compliance of treatment.
There are studies that have demonstrated the
efficacy10 and tolerability of topical treatments with
a neoadyuvant8 or sequential/combined
use9. Sequential use of topical chemotherapies
(imiquimod and PDT) can be considered an effective alternative that can
contribute to tolerate treatment schedules, reduce recurrences and
favour control disease.