An autopsy case of metastatic extramammary Paget’s disease treated with multimodality treatment including anti-HER2 therapy: What is the clinical and pathological significance of trastuzumab to the patient?

doi:10.4236/mc.2013.24008

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Vol.2, No.4, 66-68 (2013) Modern Chemotherapy

http://dx.doi.org/10.4236/mc.2013.24008

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

patient?

Noriko Yoshimura1*, Koji Arihiro2, Shunsuke Takahagi3, Michihiro Hide3

1Department of Surgery, Hiroshima General Hospital, Hiroshima, Japan; *Corresponding Author: [email protected]

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

cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

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

1. INTRODUCTION

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.

2. CASE

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

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.

3. DISCUSSION

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

positive.

(a) (b)

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

N. Yoshimura et al. / Modern Chemotherapy 2 (2013) 66-68

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.

4. CONCLUSION

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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