2Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
3Department of Pathology, En Chu Kong Hospital, New Taipei City, Taiwan
Keywords: Extramammary Paget’s Disease; Axilla; Estrogen Receptor; Progesterone Receptor
The histopathology of this biopsy was characterized by clusters of neoplastic cells with pale cytoplasm, marked nuclear pleomorphism, hyperchromasia, and distinct nucleoli in the epidermis (Figure 2).There was no invasive carcinoma identified on multiple levels within the dermis or subcutis and the underlying apocrine sweat glands were normal. Immunohistochemically, the neoplastic cells are positive for ER, PR, and weakly positive for Her2 (Figure 3-5). Integrating the histological findings and immunohistochemical profile, the diagnosis of pigmented EMPD was made. The possibility of
The pigmented variant of EMPD is an extremely rare entity with only a few well-documented cases previously reported in the literature (Table 1) [1-12]. The reported cases of pigmented EMPD occurred mostly in females with an average age of 63 years (range 43–83 years), and have involved mostly the vulvar or perineal region. Axillary involvement of pigmented EMPD
Table 1:Pigmented EMPD in the literature |
||||||||
Study |
Year |
No |
Age |
Sex |
Site |
Cancer |
ER/PR status |
Ref |
Chiba et al. |
2000 |
2 |
52 y/o |
F |
Vulva |
Breast |
N.A. |
1 |
Gumurdula et al. |
2004 |
1 |
63 y/o |
F |
Perineum |
- |
N.A. |
2 |
Ko et al. |
2004 |
1 |
58 y/o |
M |
Scrotum |
- |
N.A. |
3 |
Hilliard et al. |
2009 |
1 |
79 y/o |
M |
Axilla |
- |
N.A. |
4 |
Petersson et al |
2009 |
1 |
43 y/o |
F |
Vulva |
- |
N.A. |
5 |
Vincent et al. |
2011 |
1 |
63 y/o |
F |
Abdomen |
Colon |
N.A. |
6 |
Lentini et al. |
2011 |
1 |
50 y/o |
F |
Vulva |
- |
N.A. |
7 |
Coras-Stepanek et al. |
2012 |
1 |
83y/o |
M |
Scrotum |
- |
N.A. |
8 |
Wang et al. |
2012 |
1 |
76 y/o |
M |
Axilla |
Prostate |
N.A. |
9 |
De la Garza Bravo et al. |
2014 |
1 |
51 y/o |
F |
Thigh |
Breast |
N.A. |
10 |
Ladak et al. |
2014 |
1 |
63 y/o |
F |
Axilla |
- |
- |
11 |
Kiavash et al. |
2019 |
1 |
74 y/o |
F |
Abdomen |
- |
N.A. |
12 |
Chen et al. |
2020 |
1 |
40 y/o |
F |
Axilla |
- |
+ |
Current case |
N.A. : not available |
The clinical relevance of this variant of EMPD resides in its potential to be misdiagnosed as malignant melanoma. The clinical differential diagnosis often includes anatypical melanocytic neoplasm or a pigmented Bowen’s disease. The presenceof intraepidermal pagetoid cells containing cytoplasmic melanin pigment and the absence of anunderlying carcinoma may prompt the histological diagnosis of melanoma.The presence of dermal melanophages,inflammation, and fibrosis also mimick the regression of a dermal melanocytic component unless pigmented variant of EMPD is considered in the differential diagnosis. With the advent of immunohistochemical stainings, Paget cells usually stain positively for CK7, CK20, CAM 5.2, EMA, CEA, Her2/neu, BER-EP4, GCDFP15 (BRST2), or mucicarmine[7]. These cells are almost uniformly negative for melanocytic markers including S100, HMB45, MART1/Melan-A, and MITF.
The role of ER and PR in EMPD is still unclear. Zhou et al. reported the ER expression was 19.44% in EMPD [16], which was higher than the previous rate in literature. Their data confirmed that the ER was rarely detected in EMPD.However, no significant difference in ER expression between EMPD(19.44%) and MPD (9.09%) was noted in their study. The expression of ER and PR in pigmented EMPD is not fully investigated.Ledak et al. reported a case of a 63-year-old female with axillary pigmented EMPD with positive Her2, but negative ER, and PR on immunohistochemical staining[11]. It is the only documented case describing the status of ER and PR in pigmented EMPD in previous English literature. Our case is the first reported case of pigmented EMPD on the axilla with positive ER and PR staining. We believe that the study of hormonal receptors might be a way to understand the pathogenesis of pigmented EMPD. The hormonal therapy, such as ER-inhibitor tamoxifen, may also be an alternative for selected ER-positive advanced cases.
The relationship between Paget’s cells and melanocytes in pigmented EMPD remains unclear. It is hypothesized that the pigmentation could be the result of increased reactive melanocytes near the Paget’s cells or the increased uptake of melanin from the surrounding melanocytes. The presence of reactive melanocytes within an epithelial neoplasm has been described in other cutaneous tumors, including melanoacanthomas[17,18], basal cell carcinomas [19],seborrheic keratosis, pigmented Bowen’s disease [11],and melanocytic matricoma[20].On the other hand, the pigmentation of Paget cells could be the transfer of melanin from the surrounding melanocytes.It had been shown that Basic Fibroblastic Growth Factor (bFGF) and other chemotactic factors were the key factors in the transfer of pigment from the surrounding dendritic melanocytes[21,22].These cytokine factors may play the same role in pigmented EMPD as well.
Despite the recurrence rates for genital and peri¬anal EMPD have been shown to be 32–50% and 50–70%, respectively [23], a recent study of seven cases of unilateral axillary EMPD showed no recurrence after local resection [14].It is still not clear whether the recurrence rate of the pigmented variant of EMPD may be less than that of its non-pigmented variant. Because the lesion in our patient recurred 16 months later after the primary excision,we believe it is mandatory to follow up these patients regularly. In summary, we described the unique case of pigmented EMPD in a female patient over the axillary region. We also intended to raise awareness of the potential pitfall of misdiagnosing pigmented EMPD both clinically and histologically as melanoma unless this variantof Paget’s disease is considered in the differential diagnosis. The expression of ER and PR in pigmented EMPD should be further investigated for the understanding of pathogenesis in pigmented EMPD and the potential role of adjuvant hormonal therapy in this rare disease.
- Chiba H, Kazama T, Takenouchi T, Nomoto S, Yamada S, et al. Two cases of vulval pigmented extramammary Paget's disease: histochemical and immunohistochemical studies. Br J Dermatol. 2000;142:1190–1194.
- GumurdulaD, Sung CJ, Lawrence WD. Pathologic quiz case: a 63-year-old woman with a pigmented perineal lesion. Extramammary Paget disease. Arch Pathol Lab Med. 2004;128(1):e23–24.
- Ko MJ, Hsiao CH, Tseng CJ, Liao YH. Pigmented extramammary Paget's disease. Dermatol Sin.2004;22:321–326.
- Hilliard NJ, Huang C, Andea A. Pigmented extramammary Paget’s disease of the axilla mimicking melanoma: case report and review of the literature. J CutanPathol. 2009;36(9):995–1000.
- Petersson F, Ivan D, Kazakov DV, Kazakov DV, Michal M, et al. Pigmented Paget disease–a diagnostic pitfall mimicking melanoma. Am J Dermatopathol. 2009;31(3):223–226.
- Vincent J, Taube JM. Pigmented extramammary Paget disease of the abdomen: a potential mimicker of melanoma. Dermatol Online J. 2011;17(8):13.
- Lentini M, Le Donne M. Asymmetrically pigmented patch on the vulvoperineal area: a quiz. Pigmented extramammary Paget’s disease. ActaDermVenereol. 2011;91(3):380–381.
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- Bravo MM, Curry JL, Cabala CA, Ivan DS, Drucker C, et al. Pigmented extramammary Paget disease of the thigh mimicking a melanocytic tumor: report of a case and review of the literature. J CutanPathol. 2014;41(6):529-535.
- Ladak A, Bramley M, Titi S. Unilateral Pigmented Extramammary Paget's Disease of the Axilla Associated with a Benign Mole: A Case Study and a Review of Literature. Korean J Pathol. 2014;48(4):292-296.
- Kiavash K, Kim S, Thompson AD. "Pigmented Extramammary Paget Disease"-A Potential Mimicker of Malignant Melanoma and a Pitfall in Diagnosis: A Case Report and Review of the Literature. Am J Dermatopathol. 2019;41(1):45-49.
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- Chiu CS, Yang CH, Chen CH. Extramammary Paget's disease of the unilateral axilla: a review of seven cases in a 20-year experience. Int J Dermatol. 2011;50(2):157–160.
- Ohno H, Hatoko M, Kuwahara M, Ohnuma Y, Iida T, et al. Two cases of unilateral axillary Paget's disease. J Dermatol. 1998;25(4):260–263.
- Zhou S, Zhong W, Mai R, Zhang G. Mammary and Extramammary Paget's Disease Presented Different Expression Pattern of Steroid Hormone Receptors. Biomed Res Int. 2017;2017:3768247.
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- Williams CM, Bozner P, Oliveri CV, Horenstein MG. Melanocytic matricoma: case confirmation of a recently described entity. J CutanPathol. 2003;30(4):275–278.
- Konomi K, Imayama S, Nagae S, Terasaka R, Chijiiwa K, Yashima Y. Melanocyte chemotactic factor produced by skin metastases of a breast carcinoma. J SurgOncol. 1992;50:62–66.
- Saitoh K, Saga K, Okazaki M, Maeda K. Pigmented primary carcinoma of the breast: a clinical mimic of malignant melanoma. Br J Dermatol. 1998;139(2):287–290.
- Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s disease. Br J Dermatol. 2000;142(1):59-65.