apocrine carcinoma of the mammary skin

doi: 10.1111/j.1346-8138.2010.00816.x Journal of Dermatology 2010; 37: 350–354

CASE REPORT

Apocrine gland carcinoma of the mammary skinconcomitant with pagetoid phenomenon

Keiko USUI,1 Toyoko OCHIAI,1 Ikuko ABE,1 Haruko NISHIO,1 Kana TOGO,1

Motoo YAMAGATA2

Departments of 1Dermatology and 2Surgery, Surugadai Nihon University Hospital, Surugadai, Tokyo, Japan

ABSTRACT

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To

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35

We reported a 52-year-old woman with an apocrine gland carcinoma of the mammary skin concomitant with page-

toid phenomenon. She had a 23-year history of a small nodular lesion on the lower left part of her right breast with a

1-year history of the pigmented plaque spreading peripherally around the nodule. Our diagnosis revealed that the

nodule was an apocrine gland carcinoma and the intraepidermal neoplastic cells with pagetoid spread in the

pigmented plaque were derived from the apocrine gland carcinoma. No Paget’s cells were detected in the right

nipple, and no tumor cells were observed in the sentinel lymph node and underlying mammary gland tissue. We also

investigated the immunohistochemical changes in this case. They showed that both intraepidermal neoplastic cells

with pagetoid spread and tumor cells of the apocrine gland carcinoma were positive with cytokeratin-7 and human

epidermal growth factor receptor-2 (HER-2) ⁄neu overexpression. The results of the present study conclude that the

intraepithelial spread of tumor cells in the mammary skin distant from the nipple occurred as a pagetoid phenome-

non, and that HER-2 may have a key role in pagetoid phenomenon of an underlying apocrine gland carcinoma, as

well as in mammary Paget’s disease.

Key words: apocrine gland carcinoma, breast, cytokeratin 7, human epidermal growth factor receptor-2 ⁄ neu, pagetoid

phenomenon.

INTRODUCTION

An apocrine gland carcinoma sometimes shows

epidermotropism forming intraepidermal spread, the

so-called pagetoid phenomenon.1 We describe a rare

case of apocrine gland carcinoma of the mammary

skin concomitant with pagetoid phenomenon and

investigate the histological and immunohistochemical

changes. The implications of these findings are also

discussed.

CASE REPORT

A 52-year-old woman visited our hospital in August

2006 with a rash on the lower left part of her right

orrespondence: Keiko Usui, M.D., Department of Dermatology, Surugad

kyo 101-8309, Japan. Email: [email protected]

eceived 16 May 2008; accepted 6 November 2009.

0

breast. She first noticed a small verrucous eruption at

the site during her second pregnancy, and it had

persisted for 23 years. The eruption had been asymp-

tomatic. However, 1 year before her visit to our hospi-

tal, a pigmented lesion extended peripherally around

the eruption. Physical examination revealed a

9 mm · 9 mm reddish, slightly elevated nodule on

the lower left part of her right breast. The nodule was

surrounded by a pigmented plaque, which was

57 mm · 45 mm in diameter and was encircled by a

pale brownish macule (Fig. 1). The macule had an

irregular border and showed no induration. The pig-

mented lesion exhibited shading from light brown to

darker brown. In addition, there were depigmented

areas within the pigmented plaque. Although the right

ai Nihon University Hospital, 1-8-13 Surugadai, Kanda, Chiyoda-ku,

� 2010 Japanese Dermatological Association

Figure 1. A 9 mm · 9 mm reddish, slightly elevated nodule(arrow) was situated approximately 4 cm away from thepatient’s right nipple. It was surrounded by a 57 mm ·45 mm pigmented plague, which was encircled by a palebrownish macule.

Apocrine gland carcinoma of the mammary skin

border of the macule reached her right areola, her

right nipple appeared normal. The lymph nodes were

not palpable in either axillary region. Mammary mag-

netic resonance imaging and positron emission

tomography examination did not detect lesions in her

right breast or enlarged lymph nodes. Her general

condition was good, and the results of routine labora-

tory studies were all within normal ranges. Serum

carcinoembryonic antigen levels were normal. Two

biopsies were taken from the nodule and the neigh-

boring pigmented plaque. Based on these patho-

logical findings, the patient was treated with broad

excision of the lesion including 3 cm of surrounding

skin and underlying mammary gland tissue. We also

performed sentinel node biopsy. At 7 months follow-

ing surgery, all symptoms had disappeared.

METHODS

Formalin-fixed and paraffin-embedded biopsy speci-

mens, surgical specimens and sentinel lymph node

tissues were examined histologically. Routine hema-

toxylin–eosin and periodic acid-Schiff (PAS) staining

was performed on each specimen. Immunohisto-

chemical studies were performed with monoclonal

antibody against cytokeratin-7, cytokeratin-20 (Nic-

hirei, Tokyo, Japan), anti-estrogen receptor mouse

monoclonal antibody (Ventana, Tucson, AZ, USA),

gross cystic disease fluid protein-15 (Novocastra,

Newcastle upon Tyne, UK) and anti-Ki-67 (DakoCyto-

mation, Glostrup, Denmark), and polyclonal antibody

against S-100 protein (Nichirei). Paraffin-embedded


tissue sections were also studied by immunohisto-

chemistry for human epidermal growth factor recep-

tor-2 (HER-2) overexpression. Sections were

examined using anti-human HER-2 ⁄neu mouse poly-

clonal antibody (Hercep Test; DakoCytomation).

Staining intensity of tumor cell membranes in the

majority of tumor cells was graded as 3+, focal strong

membrane staining was graded as 2+, focal low

intensity membrane staining was graded as 1+, and

granular cytoplasmic staining or no staining of tumor

cells was graded as 0.

RESULTS

Histopathological study of the pigmented plaque

revealed numerous intraepidermal neoplastic cells

with pagetoid spread in a basal layer, as well as in the

epithelium of hair follicles, both alone and in groups.

These intraepidermal neoplastic cells had hyper-

chromatic and irregularly shaped nuclei and eosino-

philic cytoplasm (Fig. 2), and were PAS-positive and

diastase-resistant. The dermis showed marked

inflammatory infiltration by lymphocytes and melano-

phages. The nodular lesion revealed atypical cells

proliferating in the upper dermis in sheets and cords

with glandular lumina (Fig. 3a). The cytoplasm of

the tumor cells was eosinophilic and PAS-positive

diastase-resistant granules, and showed decapitation

secretion into the lumina (Fig. 3b). The overlying

epidermis on the periphery of the nodule showed a

few scattered pagetoid cells (Fig. 3c). In the sentinel

lymph node and underlying mammary gland tissue,

no tumor cells were observed. No Paget’s cells were

detected in the right nipple. These findings were con-

sistent with apocrine gland carcinoma of the mam-

mary skin concomitant with pagetoid phenomenon.

Immunohistochemical staining revealed that intra-

epidermal neoplastic cells with pagetoid spread and

tumor cells of apocrine gland carcinoma in the nodu-

lar lesion were positive for cytokeratin-7 (Fig. 4a,b),

but negative for cytokeratin-20 and S-100 protein.

Gross cystic disease fluid protein-15 was weakly

positive for tumor cells of apocrine gland carcinoma

and negative for intraepidermal neoplastic cells. As

well, the mean percentage of the Ki-67 labeling

index was 10.0% in tumor cells of apocrine gland

carcinoma and 9.0% in the intraepidermal neoplastic

cells. Tumor cells expressed estrogen receptors.

351

(a)

(b)

Figure 2. (a) Pigmented plaque showing numerous intraepi-dermal neoplastic cells with pagetoid spread in the basallayer and epithelium of hair follicles (hematoxylin–eosin [HE],original magnification ·40). (b) High-magnification view of (a)showing intraepidermal neoplastic cells had hyperchromaticand irregularly shaped nuclei and eosinophilic cytoplasm(HE, original magnification ·100).

(a)

(b)

(c)

K. Usui et al.

HER-2 ⁄neu protein overexpression was also seen,

with a 3+ staining pattern in intraepidermal neoplastic

cells and a 2+ staining pattern in tumor cells (Fig. 5).

Figure 3. (a) Nodule showing atypical cells proliferating inthe upper dermis in sheets and cords with glandular lumina(hematoxylin–eosin [HE], original magnification ·40). (b) High-magnification view of (a) showing tumor cells formingglandular structures with decapitation section (HE, originalmagnification ·400). (c) The overlying epidermis on theperiphery of the nodule showing a few scattered pagetoidcells (HE, original magnification ·100).

DISCUSSION

We reported a rare case of apocrine gland carcinoma

of the mammary skin concomitant with pagetoid phe-

nomenon. In our case, the nodular lesion first

appeared on the lower left part of the right breast

23 years previously. The pigmented plaque then

spread peripherally around the nodule. Histopatho-

logical examination showed that the nodule was an

apocrine gland carcinoma, and that the intraepider-

mal neoplastic cells with pagetoid spread in the

pigmented plaque derived from this carcinoma. No

tumor cells were observed in her right nipple and the

352

underlying mammary gland tissue. The possibility of a

supernumerary breast was ruled out as the nodular

lesion in our case was lateral to the milk line.


(a)

(b)

Figure 4. Immunohistochemical findings with cytokeratin-7.Intraepidermal neoplastic cells with pagetoid spread in thepigmented plaque (a) and tumor cells in the nodular lesion (b)are positively stained.

(a)

(b)

Figure 5. Immunohistochemical findings with anti-humanHER-2 ⁄neu mouse polyclonal antibody. Intraepidermal neo-plastic cells with pagetoid spread in the pigmented plague (a)show a 3+ staining pattern and tumor cells in the nodularlesion (b) show a 2+ staining pattern.

Apocrine gland carcinoma of the mammary skin

Apocrine carcinomas are a malignant neoplasm

with apocrine differentiation. According to a textbook

of Neoplasms with Apocrine Differentiation by Reque-

na et al.,2 histological findings of our case revealed a

ductal carcinoma. Apocrine carcinomas are typically

centered on the deeper dermis and tend to spread

into the subcutaneous tissue. Pagetoid spread also

occurs as shown in our case. We found several

reports of pagetoid phenomenon.3,4 All of these arti-

cles, however, described lesions situated in regions

other than the breast. Apocrine adenoma may be pre-

cursors of apocrine carcinoma. Miyamoto et al.5

reported that apocrine carcinoma, adenoma and

hyperplasia may be successive steps in a linear

progression to a carcinoma. We presumed that the

nodular lesion in our case had become malignant at

some point during the previous 23 years. However,


we were unable to find any evidence of the coexis-

tence of adenoma or hyperplasia situated within or

surrounding the carcinoma.

In this study, we confirmed HER-2 overexpression

in the intraepidermal neoplastic cells with pagetoid

spread and in the tumor cells of the apocrine gland

carcinoma. Tumor cells were also positive for

estrogen receptors. Immunohistochemical staining

patterns failed to distinguish our case from breast

carcinoma. As the mammary gland represents a

modified apocrine gland,6 where tumor cells locate

is conclusive evidence for distinguishing apocrine

gland carcinoma from breast carcinoma. HER-2

proto-oncogene is a member of the growth factor

receptor gene family located on the long arm of

chromosome 17. The 185-kd transmembrane glyco-

protein encoded by this gene is involved in the

tyrosine kinase signaling pathway for epithelial

proliferation.7 Numerous studies on HER-2 gene

353

K. Usui et al.

overexpression have been performed in patients with

invasive breast cacinoma.8,9 Although HER-2 over-

expressing breast carcinoma shows aggressive clini-

cal behavior, the anti-HER-2 antibody trastuzumab

has been demonstrated to improve patient survival

and control the disease.10

Recent studies have indicated a high rate of HER-2

gene amplification and a good correlation between

HER-2 ⁄neu protein overexpression and HER-2 gene

amplification in mammary Paget’s disease. It is

widely believed that the spread of the neoplastic cells

in Paget’s disease is induced by a motility factor that

acts through the HER-2 ⁄new receptor. Schelfhout

et al.11 identified heregulin-a as a motility factor

released by normal epidermal keratinocytes that acts

on the HER-2 ⁄neu receptor, and induces chemotaxis

and subsequent spread of Paget’s cells throughout

the nipple epidermis. Recognition of HER-2 over-

expression is essential, as it could lead to the intro-

duction of trastuzumab therapy for patients with

mammary Paget’s disease, as well as breast carci-

noma. In contrast, inconsistent results have been

reported in extramammary Paget’s disease.12,13

In conclusion, the results of the present case sug-

gest that the intraepithelial spread of tumor cells in

the mammary skin distant from the nipple occurred

as a pagetoid phenomenon, and that HER-2 may play

a key role in pagetoid phenomenon of an underlying

apocrine gland carcinoma, as well as in mammary

Paget’s disease.

REFERENCES

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2 Requena L, Kiryu H, Ackerman AB. Neoplasms withApocrine Differentiation. Lippincott-Raven Publishers,Philadelphia 1998.

3 Fligiel Z, Kaneko M. Extramammary Paget’s disease ofthe external ear canal in association with ceruminousgland carcinoma. Cancer 1975; 36: 1072–1076.

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5 Miyamoto T, Hagari Y, Inoue S et al. Axillary apocrinecarcinoma with benign apocrine tumors: a case reportinvolving a pathological and immunohistochemical studyand review of the literature. J Clin Pathol 2005; 58: 757–761.

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7 Akiyama T, Sudo C, Ogawa H et al. The product ofc-erbB-2 gene. A 185-kilodalton glycoprotein with tyro-sine kinase activity. Science 1986; 232: 1644–1646.

8 Slamon DJ, Leyland-Jones B, Shak S et al. Use ofchemotherapy plus a monoclonal antibody againstHER2 for metastatic breast cancer that overexpressesHER2. N Engl J Med 2001; 344: 783–792.

9 Carney WP, Leitzel K, Ali S et al. HER-2 ⁄ neu diagnosticsin breast cancer. Breast Cancer Res 2007; 9: 207.

10 Bianco MK, Vasef MA. HER-2 gene amplification inPaget disease of the nipple and extramammary site: achromogenic in situ hybridization study. Diagn MolPathol 2006; 15: 131–135.

11 Schelfhout VR, Coene ED, Delaey B et al. Pathogenesisof Paget’s disease: epidermal heregulin-alpha, motilityfactor, and the HER receptor family. J Natl Cancer Inst2000; 92: 622–628.

12 Meissner K, Riviere A, Haupt G et al. Study of neu-protein expression in mammary Paget’s disease withand without underlying breast carcinoma and in extra-mammary Paget’s disease. Am J Pathol 1990; 137:1305–1309.

13 Brummer O, Stegner HE, Bohmer G et al. HER-2 ⁄ neuexpression in Paget disease of the vulva and the femalebreast. Gynecol Oncol 2004; 95: 336–340.


apocrine carcinoma of the mammary skin

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