Vol.2, No.4, 66-68 (2013) Modern Chemotherapy
An autop sy case of met astatic extramammary Paget’s
disease treated with multimodality treatment
including anti-HER2 therapy: What is the clinical and
pathological significance of trastuzumab to the
Noriko Yoshimura1*, Koji Arihiro2, Shunsuke Takahagi3, Michihiro Hide3
1Department of Surgery, Hiroshima General Hospital, Hiroshima, Japan; *Corresponding Author: yoshimuranoriko32@gmail.com
2Department of Pathology, Hiroshima University Hospital, Hiroshima, Japan
3Department of Dermatology, Hiroshima University Hospital, Hiroshima, Ja pa n
Received 1 October 2013; revised 21 October 2013; accepted 27 October 2013
Copyright © 2013 Noriko Yoshimura et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Advanced Extramammary Paget’s disease
(AEMPD) shows a poor prognosis despite multi-
modality therapy. In recent y ears, it is sugge sted
that anti-HER2 therapy may be promising for
HER2-positive AEMPD. We herein present an
autop sy case of a p atient with AEMPD treated with
multimodality treatment including anti-HER2 the-
rapy. A 78-year-old man who diagnosed with
AEMPD died after surgery and systemic chemo-
therapy including anti-HER2 therapy (trastuzu-
mab). The metastatic skin lesions were immno-
histologically HER2-positive. While the patients
were administrated trastuzumab plus taxan (do-
cetaxel, and paclitaxel) regimen, the metastatic
skin lesion decreased, however, brain metasta-
ses were found in his brain and trastuzumab is
discontinued. The skin metastasis rapidly spread
over his body, leading to weakness, and he
eventually died. At autopsy, the lesions of EMPD
were extended distant organs including brain,
although each metastasis was small and as-
ymptomatic. The wide lesion of skin metastasis
was exacerbated after discontinuation of tras-
tuzumab, and transudate was observed due to
the extensive necrosis and erosion. Our au topsy
findings showed one progressive pattern of
AEMPD, and indicated what is the clinical and
pathological significance of anti HER2 therapy
for HER2-positive AEMPD.
Keywords: Extramammary Paget’s Disease;
HER2; Autopsy
Extramammary Paget’s disease (EMPD) is a distinct
type of skin carcinoma originating in the apocrine gland.
Advanced EMPD (AEMPD) cases show a poor progno-
sis despite multimodality therapy. In recent years, some
authors reported the overexpression of human epidermal
growth factor receptor 2 (HER2) [1-3] in AEMPD, thus
suggesting that anti-HER2 therap y may be promising for
the disease. We herein present an autopsy case of a pa-
tient with AEMPD who was treated with multimodality
therapy, including trastuzumab. The detailed clinical
presentation of this patient has been reported previously
[4]. In this letter, we highlight the autopsy findings of our
patient and examine the clinical and pathological sig-
nificance of trastuzumab to the patient.
A 78-year-old male patient presented with erythema
on the scrotum, which he had first noted almost five
years prior. The erythema had gradually extended, these
lesions were diagnosed as EMPD by a skin biopsy 28
months before his death and skin resection and dissection
of the left inguinal lymph nodes were performed. After
surgery, the patient was treated with systemic chemothe-
rapy using Mitomycin (20 mg/m2) + 5-FU (1000 mg/m2)
at first, and then weekly with Docetaxel (60 mg/m2).
However, the skin recurrence worsened. At this point, a
Copyright © 2013 SciRes. OPEN A CCESS
N. Yoshimura et al. / Modern Chemotherapy 2 (2013) 66-68 67
biopsy of these skin lesions was performed, and it re-
vealed HER2 overexpression on the tumorcellular mem-
brane. The patient was therefore administrated an
anti-HER2 drug, trastuzumab (4 kg/kg), followed by a 2
mg/kg maintenance dose at weekly intervals in combina-
tion with Taxanes (Docetaxel and Paclitaxel) according
to a protocol for HER2-positive metastatic breast cancer
beginning 14 months prior to his death. The metastatic
skin lesion rapidly decreased in size. However, multiple
small spots were found in his brain by MRI 10 months
before his death, which were diagnosed as brain metas-
tases. The regimen was then shifted to low dose 5-FU
(1000 mg/m2) and Cisplatin (15 mg/m2). Radiotherapy
for the brain was performed. The skin recurrence rapidly
spread over his body, and he suffered from gradual de-
bilitation, pneumonia, a urinary tract in fection, and ev en-
tually died.
We performed an autopsy on the patient. For the skin
lesion, HER2-positive skin recurrence was observed ex-
tending to the vulva, bilateral thighs and the lower ab-
domen (Figure 1). These exacerbated after discontinua-
tion of trastuzumab, and transudate was observed due to
the extensive necrosis and erosion. For brain metastases,
some small lesions were detected in the basal ganglion,
hippocampus, cerebellum, and pons. Some of them ex-
hibited vacuolar degeneration, indicating the effect of
whole brain radiotherapy (Figure 2). In the lungs, acute
bronchopneumonia and acute diffuse alveolar damage
with pleural effusion were detected. In the kidneys, acute
pyelonephritis and mild acute tubular necrosis were ob-
served. Other metastases were found in bilateral lungs,
the pancreas, and lymph nodes.
Our patient died 28 months after the diagnosis of
AEMPD. To the best of our knowledge, there are no re-
ports about autopsy case of AEMPD treated with anti-
HER2 therapy. Generally, most AEMPD cases are diffi-
cult to treat even with multimodality therapy. The mor-
tality rate associated with progressive EMPD is 13% -
(a) (b)
Figure 1. Histopathologic findings: (a) H.E stain ×40, (b) Im-
munohistochemical stain of skin lesion revealed HER2 were
(a) (b)
(c) (d)
Figure 2. Macroscopic findings: (a) Cerebrum; (b) Cerebellum.
small, multipulmetastatic nodules were found. Histopathologi-
cal findings; (c) Basal ganglion (H.E stain ×40); (d) hippocam-
pus (H.E stain ×100). The vacuolar degenerations were found
in some metastasis.
18% [5,6], and the 5-year survival rate of AEMPD is
reported to be 72% [7]. The general pattern of metastasis
in EMPD is lymphogenous, and less often, hematoge-
nous spread. Brain metastasis is relatively uncommon.
Furthermore, the detection of brain metastasis during the
course of disease is unlikely. There is no established che-
motherapy regimen for AEMPD and various regimens
have been administered, such as topical 5-Fluorouracil,
Mitomycin C, Cisplatin, Docetacel, etc. As noted previ-
ously, 20% - 60% of EMPD show HER2 expression,
which is approximately the same or higher percentage
than primary breast cancers. The combination of con ven-
tional chemotherapy regimens with anti-HER2 drugs is
therefore expected to improve the overall survival for
AEMPD patients. Previous reports show favorable local
control, but further investigations, such as those evaluat-
ing the response rate or survival, are difficult due to the
relative rarity of the condition. In our patient, the use of
trastuzumab plus taxanes showed a dramatic effect on the
skin metastasis, but brain metastases developed. Is this
situation coincidental? Trastuzumab does not cross the
blood-brain barrier and it has been reported that patients
with HER2-positive breast cancer have a significantly
higher incidence of brain metastasis after treatment with
trastuzumab [8]. Nevertheless, it has been suggested that
the metastasis of EMPD to the brain is rare. However,
since each metastasis was small and did not lead to neu-
rological symptoms, we may not have had to discontinue
administering trastuzumab. It might have been the tran-
sudate from the skin metastasis that caused low nutrient
Copyright © 2013 SciRes. OPEN A CCESS
N. Yoshimura et al. / Modern Chemotherapy 2 (2013) 66-68
Copyright © 2013 SciRes. OPEN A CCESS
condition, generalized weakness, and eventually death.
In many AEMPD cases, there have been no reports on
lethal events such as hemorrhage due to metastases to
other organs that resulted in death. Rather, patients pro-
gressively weaken and die. Hence, we suggest that con-
trol of skin lesions be assigned a priority instead of fo-
cusing on treating small metastases in other organs.
New anti-HER2 drugs have been developed recently.
Lapatinib, for example, is a small molecule anti-HER2
agent used for breast cancer which is known to penetrate
the blood-brain barrier and contribute to overall survival
of patients with br ain metastases. Although clinical indi-
cations need to be clearer and the cost might hinder posi-
tive use, lapatinib could be an effective treatment strat-
egy for AE MPD.
We confirmed one progressive pattern of AEMPD
treated with multimodality therapy, including anti-HER2
therapy. More amassed reports and further investigations
will be necessary.
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