© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
J Cutan Pathol 2014: 41: 529–535 doi: 10.1111/cup.12333 John Wiley & Sons. Printed in Singapore
Journal of Cutaneous Pathology
Pigmented extramammary Paget disease of the thigh mimicking a melanocytic tumor: report of a case and review of the literature Importance: Extramammary Paget disease (EMPD) is an uncommon tumor that presents in apocrine-rich skin as an irregular, pruritic plaque. Histopathologically, EMPD consists of an intraepidermal proliferation of atypical epithelioid cells. Rarely, the tumor cells contain intracytoplasmic melanin pigment, and the lesion clinically and histopathologically can mimic a melanocytic proliferation. Observations: A 51-year-old female with a history of breast carcinoma presented with a pigmented patch on her right thigh of 6 months duration. The clinical impression was an atypical melanocytic nevus. Histopathologic examination revealed an intraepidermal proliferation of epithelioid cells along the dermal–epidermal junction with pagetoid migration. The tumor cells exhibited increased cytoplasm containing conspicuous melanin pigment and enlarged oval-irregular nuclei. Immunohistochemical studies showed the tumor cells to be strongly and diffusely positive for cytokeratin 8/18, cytokeratin 7 and p63; focally and weakly positive for epithelial membrane antigen (EMA), but negative for cytokeratin 5/6, Cam5.2, carcinoembryonic antigen (CEA), human melanoma black 45 (HMB-45), tyrosinase and Sox-10, supporting the diagnosis of pigmented EMPD. The lesion was subsequently excised, and the patient is free of disease after 24 months. Conclusion: We present this unusual case of pigmented EMPD arising on the thigh to draw attention to the entity and to underscore the potentially misleading clinical, histopathologic and immunophenotypic features that mimic other cutaneous intraepidermal lesions. Keywords: dermatopathology, immunocytochemistry, melanocytic lesions, melanocytic neoplasms De la Garza Bravo MM, Curry JL, Torres-Cabala CA, Ivan DS, Drucker C, Prieto VG, Tetzlaff MT. Pigmented extramammary Paget disease of the thigh mimicking a melanocytic tumor: report of a case and review of the literature. J Cutan Pathol 2014; 41: 529–535. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Mammary Paget disease (MPD) was first described in 1874 by Sir James Paget.1 – 4 In approximately 95% of the cases, it represents an intraductal extension of underlying breast carcinoma cells into the epidermis
Maria M. De la Garza Bravo1 , Jonathan L. Curry2,3 , Carlos A. Torres-Cabala2,3 , Doina S. Ivan2,3 , Carol Drucker3 , Victor G. Prieto2,3 and Michael T. Tetzlaff2 1
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA, 2 Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, and 3 Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael T. Tetzlaff Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Unit 85, Houston, TX 77030, USA Tel: 713-792-2585 Fax: 713-745-0778 e-mail: [email protected] Accepted for publication February 21, 2014
of the nipple and areola through the main lactiferous ducts. MPD is rare and occurs in only 1–5% of all mammary carcinomas. MPD can also be due to direct invasion of the epidermis by a subjacent
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De la Garza Bravo et al. infiltrating carcinoma.5 – 7 It has been previously suggested that in the absence of an underlying mammary ductal carcinoma, MPD originates from an intraepidermal glandular cell, the Toker cell.5 – 10 Extramammary Paget disease (EMPD) was first described by Crocker in 1889.11 EMPD is also a rare condition, most commonly affecting patients in their 6–8 decades of life and typically presenting as multifocal, well-circumscribed, pruritic, erythematous plaques or macules12 – 15 in apocrinerich skin, including the vulva, scrotum, axillae, groin and perianal region.13,14 Clinically, EMPD mimics seborrheic dermatitis, Bowen’s disease, psoriasis, intertrigo, eczema or tinea.3,14 – 18 The vulva is the most common location for EMPD in women followed by the perianal region.15 EMPD rarely presents on the abdomen, thigh or face and even more uncommonly presents as a pigmented lesion.14,15 Pigmented EMPD was first described clinically by Cuberson and Horn19 and represents an exceedingly rare lesion: only 10 well-documented cases have been reported so far in the literature,1,6,12,14,15,20,21 although this low number likely represents underreporting of the lesion. Pigmented EMPD presents as an irregular, diffusely pigmented plaque or macule, which clinically can mimic a melanocytic lesion.1,6,12,14,15,20,21 Histopathologically, pigmented EMPD resembles other forms of MPD and EMPD, except the intraepidermal tumor cells typically contain varying amounts of finely granular intracytoplasmic melanin pigment, and there are usually melanophages in the subjacent superficial dermis.5,15 Here, we present an unusual case of pigmented EMPD arising on the thigh of a 51year-old female and summarize the literature on pigmented EMPD. Case report A 51-year-old female with a history of invasive ductal carcinoma 3 years prior presented with a 3 × 6 mm irregularly pigmented brown patch on the right thigh, which she described had been slowly enlarging over the past 6 months. Dermatoscopic evaluation by an experienced dermatologist revealed an asymmetric and irregular pigment network. The clinical impression was that of an atypical melanocytic nevus. Examination of the shave biopsy specimen revealed a disorganized intraepidermal proliferation of single and nested epithelioid cells with pagetoid migration, involving the full thickness of the suprabasal epidermis (Fig. 1A-B). The tumor cells exhibited conspicuous cytologic atypia, including abundant cytoplasm containing prominent fine brown melanin pigment and enlarged, irregular pleomorphic nuclei with occasionally conspicuous
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nucleoli (Fig. 1B). Dermal invasion was not identified. Immunohistochemical studies showed that the tumor cells were strongly and diffusely positive for cytokeratin 7 (Fig. 1C), cytokeratin 8/18 (Fig. 1D) and p63 (Fig. 1H); the tumor cells exhibited variable, weak positivity for epithelial membrane antigen (Fig. 1G). The tumor cells were negative with special studies for intracytoplasmic mucin (data not shown), and for immuno-antibodies for cytokeratin Cam5.2 (Fig. 1F; strongly highlighted scattered intraepidermal Merkel cells), cytokeratin 5/6 (Fig. 1E; highlights surrounding keratinocytes), carcinoembryonic antigen (data not shown), an anti-melanocytic cocktail containing anti-human melanoma black 45 (HMB-45) and anti-tyrosinase (Fig. 1I), and Sox-10 (Fig. 1J). Together with the morphology, these features supported the diagnosis of pigmented EMPD. The patient underwent subsequent wide local excision with 5 mm clinical margins followed by Mohs-assisted excision on the surrounding tissue. Persistent EMPD was not identified in either the central Mohs-debulking specimen (examined in permanent sections) or the peripheral margins (examined by frozen section). Two months after the resection, the patient began a 30-day course of topical imiquimod therapy (5% Aldara applied to the area 5 days/week). An extensive gynecologic and gastroenterologic work-up revealed no underlying carcinoma. The patient is currently free of disease without evidence of local recurrence after 24 months of follow-up. Discussion EMPD is a rare disease that typically presents as an erythematous patch in apocrine-rich skin such as vulva, scrotum, groin, perineum and axillae.1,5,14,21,22 Two types of EMPD are recognized. Type 1 (a.k.a. primary type) includes the vast majority of the cases and is thought to arise as epidermal colonization from transformed cells of underlying cutaneous apocrine glands. Type 1 EMPD is therefore not associated with underlying visceral malignancies.6,22 In type 2 (a.k.a. secondary type), the tumor cells arise as either a direct extension or epidermotropic metastasis from a visceral carcinoma.6,15 Histopathologically, EMPD consists of a disorganized intraepidermal proliferation of malignant epithelioid cells involving the full thickness of the suprabasal epidermis; invasion of the subjacent dermis can occasionally be seen. The tumor cells in EMPD typically stain positively for periodic acid-Schiff (diastase resistant), mucicarmine, aldehyde fuchsin and/or Alcian blue.3,15,22 Immunohistochemically, the tumor cells exhibit positivity for epithelial markers, including cytokeratin 7,
Pigmented Paget disease
Fig. 1. Pigmented extramammary Paget disease. A) Intraepidermal proliferation of single and nested atypical epithelioid cells with increased cytoplasm containing granular brown pigment and enlarged, oval-irregular nuclei (hematoxylin/eosin, ×100). B) Higher magnification shows tumor cells with increased clear cytoplasm with conspicuous brown melanin pigment (hematoxylin/eosin, ×400). Immunohistochemical studies demonstrate that the tumor cells are positive for (C) cytokeratin 7 (CK7), and (D) CK8/18. The tumor cells are negative for CK5/6 (E) and Cam5.2 (F; strongly highlighted scattered intraepidermal Merkel cells and intracytoplasmic melanin pigment is present). The tumor cells exhibit focal positivity for epithelial membrane antigen (EMA; G) and are positive for p63 (H). The tumor cells lack reactivity with a melanocytic cocktail containing antibodies for both human melanoma black 45 (HMB-45) and tyrosinase (I). The tumor cells are also negative for SOX-10 (J). All immunohistochemical studies are displayed at ×200 magnification.
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De la Garza Bravo et al. Table 1. Summary of immunohistochemical features of mammary and extramammary Paget disease and their mimickers
MPD EMPD SCCIS SCC, NOS (including pagetoid SCC) SSM
CK7+ cases/ total (%)
Cam5.2+ cases/ total (%)
Ber-EP4+ cases/ total (%)
p63+ cases/ total (%)
HMB-45+ cases/ total (%)
S100+ cases/ total (%)
101/102 (99) 100/102 (98) 8/73 (11) 24/77 (31)
38/39 (97) 60/60 (100) 4/37 (11) 10/50 (20)
5/9 (56) 38/40 (95) 1/18 (6) 1/50 (2)
NA 8/85 (9)* 31/31 (100) NA
0/42 (0) 0/5 (0) 0/13 (0) NA
12/20 (60) 0/5 (0) 0/1 (0) NA
0/4 (0)
0/4 (0)
NA
NA
20/20 (100)
10/10 (100)
References 8,9,25,29,30,32,34 – 36 8,9,23,24,26 – 28,30,32,34 – 37,39 25,26,28,30,33 – 35 28,31
30,32,34
EMPD, extramammary Paget disease; MPD, mammary Paget disease; NA, not available/not reported; SCCIS, squamous cell carcinoma in situ ; SSM, superficial spreading melanoma. *Includes one case of secondary EMPD
low-molecular weight cytokeratins (with Cam5.2), epithelial membrane antigen (EMA), carcinoembryonic antigen and gross cystic disease fluid protein 15.3,14,15,21 – 24 Anti-cytokeratin 7 has the highest sensitivity and specificity; however, rare cases have been reported to lack cytokeratin 7 expression in tumor cells.9 To distinguish EMPD from ‘pagetoid’ squamous cell carcinoma in situ (SCCIS), traditional markers have included cytokeratin 7 (CK7), Cam5.2, EMA and carcinoembryonic antigen – all of which are generally positive in EMPD and negative in SCCIS. Among these, EMPD is reported to exhibit diffuse and strong positivity for CK7 and Cam5.2. The results of the studies reviewed from the literature are summarized in Table 1.8,9,23 – 37 In approximately 100% of the cases studied, CK7 and Cam5.2 were positive in MPD and EMPD, although rare cases have been reported to be negative for either CK7 or Cam5.2, including the current case which was negative for Cam 5.2 (albeit positive for CK8/18).9,29 In contrast, SCCIS exhibited either CK7-positivity or Cam5.2-positivity in only ∼11% of cases, respectively. However, the percentage of CK7 and Cam5.2-positive cases increased in invasive SCC, particularly lesions that were poorly differentiated or exhibited pagetoid morphology (Table 1).28,31,33 Notably, in the invasive lesions analyzed, the overlying SCCIS component in one study was negative for CK7,31 whereas other studies have shown CK7-positivity in SCCIS associated with invasive SCC.28 Additional markers, including Ber-EP4 and p63, have been proffered to further refine this distinction for those challenging cases where markers like CK7 and Cam5.2 might lack specificity. Moderate to strong Ber-EP4-positivity was detected in approximately 95% cases of EMPD, whereas most cases of SCCIS (94%) were Ber-EP4-negative.34,35 Furthermore, only 2% of invasive SCC was Ber-EP4-positive (Table 1).28 p63 has also emerged as a useful marker
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to distinguish SCCIS from EMPD. Approximately 9% of EMPD cases analyzed were positive for p63 with most of the cases exhibiting weaker staining in the tumor nuclei compared to that seen in the surrounding keratinocyte nuclei.26,27 In contrast, p63 was strongly and diffusely positive in the tumor cells of 100% of SCCIS.26 However, important exceptions to the utility of p63 have been described. Yanai et al. demonstrated p63-positivity in the tumor cells in a case of secondary EMPD arising from an underlying urothelial carcinoma.37 Additionally, Sawada et al. described a case of ‘ectopic’ (i.e. arising in a non-apocrine site) EMPD arising on the back of a 62-year-old Japanese man in which the tumor cells exhibited strong p63-positivity.39 Together with our findings, these cases underscore important possible pitfalls in the specificity of p63 namely, that p63positivity does not necessarily exclude the diagnosis of EMPD – particularly when the lesion arises in non-apocrine locations or in association with underlying malignancy known to express p63.37,39 Future studies to assess the specificity of p63 in ‘ectopic’ EMPD are warranted to further evaluate its utility in that context. In our practice, we typically use variable combinations of Cam5.2, CK7 and p63 to distinguish SCCIS from EMPD, although the current case required additional immunohistochemical work-up to confirm the diagnosis (see below). The diagnosis of EMPD (in particular, the pigmented variant) also relies on the exclusion of melanocytic differentiation: the tumor cells should lack reactivity for melanocytic markers, including S100, MART-1, microphthalmia-associated transcription factor (MiTF) and HMB-45 antigen. In contrast, melanocytic proliferations are reactive for S100 protein, HMB-45 antigen, Melan-A, Sox-10, MiTF and/or MART-1, and very rarely express epithelial markers.1,3,6,7,18,22,29,32 In a systematic study of 20 cases of MPD, 5 cases of EMPD and 10 cases of
Pigmented Paget disease superficial spreading melanomas (SSM), Ramachandra et al. demonstrated HMB-45-positivity in 10/10 SSM, and negativity in 20/20 MPD and 5/5 EMPD (Table 1). Furthermore, all cases of SSM exhibited strong S100-positivity whereas all cases of EMPD were S100-negative.32 However, 60% of their MPD cases (12/20) showed S100-positivity, consistent with previous reports showing S100-positivity in the tumor cells of MPD in up to 10–15% of cases. These observations underscore the need to deploy at least two melanocytic markers in the panel to formally exclude melanocytic differentiation by the tumor cells.1,14,21,32 In rare cases, EMPD presents clinically as a hyperpigmented and/or hypopigmented lesion and is therefore confused clinically (as well as histopathologically) with melanocytic lesions.18 Here, we report a particularly challenging case of pigmented EMPD with several notable possible pitfalls. First, after evaluation by a dermatologist with longstanding experience in dermoscopy, the lesion was thought clinically to represent an atypical melanocytic nevus, arising also on a non-apocrine anatomic location (thigh) unusual for EMPD. Second, histopathologic evaluation revealed a proliferation of atypical epithelioid cells with conspicuous intracytoplasmic pigment, possibly further re-enforcing the possibility of misdiagnosis as a pigmented lesion. Finally, the tumor cells strongly expressed p63 and lacked expression of Cam5.2 – unusual findings in EMPD. Nevertheless, additional diagnostic workup showed the tumor cells to strongly express CK8/18 and CK7, while lacking reactivity for CK5/6 as well as melanocytic markers (HMB45, tyrosinase and Sox-10), which taken together with the clinical history, confirmed the diagnosis of pigmented EMPD. To the best of our knowledge, only 11 cases of pigmented EMPD (including the current case) have been described in the literature to date (Table 2).1,6,12,14,15,20,21 We searched for cases with the following parameters: (a) pathological diagnosis of pigmented EMPD; (b) presence of hyperpigmentation by dermatoscopy and/or histopathology; (c) immunohistochemical studies that distinguish EMPD [e.g. CK7, carcinoembryonic antigen (CEA), EMA and gross cystic disease fluid protein 15 (GCDFP15)] from melanocytic lesions (e.g. S100, Melan-A, MiTF, HMB-45, etc.); (d) tumor characteristics, including location and clinical presentation; and (e) presence or absence of an underlying adenocarcinoma. Five cases occurred in males (45%) with an average age of 72 years; and six cases developed in females (55%) with an average age of 57 years (Table 2).1,6,12,14,15,20,21 Thus, in contrast
to MPD and EMPD which occur predominantly in females, pigmented EMPD apparently exhibits an equal sex distribution. However, pigmented EMPD presents in females at an earlier average age than in males. Similar to MPD and EMPD, the vulva and scrotum (three cases each) were the most common anatomic sites involved by pigmented EMPD, followed by the axilla (two cases). However, the case reported by Vincent et al. (abdomen) and our current case (right thigh) presented in non-apocrine skin (18%), making the recognition of pigmented EMPD in these non-canonical sites even more challenging.14 There is a variable association with internal malignancy reported for EMPD.3,6,13,14,18,22,38,39 Consistent with this, only 4 of the 11 cases of pigmented EMPD (4/11; ∼36%) were associated with an internal malignancy, and this relationship appeared tenuous. One case showed some anatomic proximity (pigmented EMPD on the abdomen of a 63-year-old female) to the underlying carcinoma (colonic adenocarcinoma).14 However, in the remaining three cases, there was an apparent disconnect between the site of pigmented EMPD and the anatomic location of the internal malignancy (Table 2). For 3 of the 11 cases (including the current case), information regarding treatment and follow up was available. Each of these three cases was treated with wide local excision with negative margins and an average disease-free interval of 15 months (9–24 months follow-up).1,14 Histopathologically, all cases of pigmented EMPD resemble typical EMPD (i.e. an intraepidermal proliferation of atypical epithelioid cells with abundant cytoplasm and enlarged nuclei with prominent nucleoli). However, pigmented EMPD is characterized either by conspicuous intracytoplasmic melanin pigment in the tumor cells (described in 9/11 cases) or by increased dendritic melanocytes scattered among the tumor cells (described in 2/11 cases).1,6,12,14,15,20,21 Moreover, one case also presented with increased melanophages in the subjacent dermis.1,12 Given these various histopathologic observations, three possible mechanisms have been proposed to explain the pathogenesis of increased pigmentation observed in pigmented EMPD: (a) melanocytic colonization mediated by tumor cell-produced factors such as basic fibroblast growth factor (bFGF), melanocytestimulating hormone, epidermal growth factor, insulin and stem cell factor; (2) increased melanin pigment production by the surrounding melanocytes and transfer to the tumor cells; and/or (3) increased melanophages in the subjacent dermis.20 In summary, pigmented EMPD is a rare disease that can present as a pigmented lesion anywhere on the body. Immunohistochemical stains are helpful in recognizing this entity among melanocytic lesions.
533
534 Vulva Scrotum Scrotum Abdomen
43/F 58/M 63/M 63/F 83/M
76/M 51/F
Petersson et al. (2009)6
Vincent et al. (2011)14
Coras-Stepanek et al. (2012)20
Wang et al. (2012)15
This study (2014)
Pigmented patch
Erythematous plaque with depigmentation with sharp partly hyperpigmented margin Irregular hyperpigmented macule Variegated brown plaque
Erythematous and black-brown patch NA NA Pigmented lesion
Brown-black macule Erythematous plaque; focally pigmented Red-brown roughened area Pigmented plaque
Clinical presentation
Breast adenocarcinoma
Prostatic adenocarcinoma
NA
NA
No No Colonic adenocarcinoma
No
No No
Breast adenocarcinoma NA
Other malignancies
CK7, CK8/18, and EMA
CK7 and CEA
CK7, CEA
NA
CK7, CEA, GCDFP-15 Cam5.2, EMA, CEA CK7
CEA Pan-CK, CK7, Cam5.2, EMA and CEA. GCDFP15 and mucicarmine (weakly) CK7
Cam5.2, CEA Cam5.2, CEA
Positive
CK20, S100, Melan-A and HMB-45 CK20, CK34βE12, S100, Melan-A, and HMB-45 Cam5.2, CEA, HMB-45, tyrosinase and MITF
CK20, S100, MITF, Melan-A, and HMB-45 NA
Mart-1 and HMB-45 CK34βE12, CK20, S100, Mart-1, HMB-45 and MITF CEA, HMB-45, Melan-A and S100 CK20
HMB-45 and S100 HMB-45 and S100
Negative
Immunohistochemistry of tumor cells
CEA, carcinoembryonic antigen; CK, cytokeratin; CK34βE12, cytokeratin 34 beta E12; CK7, cytokeratin 7; CK20, cytokeratin 20; EMA, epithelial membrane antigen, F, female; GCDFP15, gross cystic disease fluid protein 15; HMB-45, human melanoma black 45; IHC, immunohistochemistry; M, male; MITF, microphthalmia-associated transcription factor; NA, not available/not reported; yr, years.
Thigh
Axilla
Scrotum
Groin
Perineum Axilla
63/F 79/M
Gumurdula et al. (2004)21 Hilliard et al. (2009)1
Vulva Vulva
Site
52/F 70/F
Age (yr)/gender
Chiba et al. (2000)12
Author (year), reference
Table 2. Summary of pigmented extramammary Paget disease reported in the literature to date
De la Garza Bravo et al.
Pigmented Paget disease Here, we present a case of pigmented EMPD arising in non-apocrine skin to highlight this entity as an important pitfall in the distinction from melanocytic tumors, including Spitz nevi and/or melanoma in situ.
Acknowledgement The authors would like to thank Ms. Kim-Anh Vu for her excellent assistance in assembling the figure.
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J Cutan Pathol 2014: 41: 529–535 doi: 10.1111/cup.12333 John Wiley & Sons. Printed in Singapore
Journal of Cutaneous Pathology
Pigmented extramammary Paget disease of the thigh mimicking a melanocytic tumor: report of a case and review of the literature Importance: Extramammary Paget disease (EMPD) is an uncommon tumor that presents in apocrine-rich skin as an irregular, pruritic plaque. Histopathologically, EMPD consists of an intraepidermal proliferation of atypical epithelioid cells. Rarely, the tumor cells contain intracytoplasmic melanin pigment, and the lesion clinically and histopathologically can mimic a melanocytic proliferation. Observations: A 51-year-old female with a history of breast carcinoma presented with a pigmented patch on her right thigh of 6 months duration. The clinical impression was an atypical melanocytic nevus. Histopathologic examination revealed an intraepidermal proliferation of epithelioid cells along the dermal–epidermal junction with pagetoid migration. The tumor cells exhibited increased cytoplasm containing conspicuous melanin pigment and enlarged oval-irregular nuclei. Immunohistochemical studies showed the tumor cells to be strongly and diffusely positive for cytokeratin 8/18, cytokeratin 7 and p63; focally and weakly positive for epithelial membrane antigen (EMA), but negative for cytokeratin 5/6, Cam5.2, carcinoembryonic antigen (CEA), human melanoma black 45 (HMB-45), tyrosinase and Sox-10, supporting the diagnosis of pigmented EMPD. The lesion was subsequently excised, and the patient is free of disease after 24 months. Conclusion: We present this unusual case of pigmented EMPD arising on the thigh to draw attention to the entity and to underscore the potentially misleading clinical, histopathologic and immunophenotypic features that mimic other cutaneous intraepidermal lesions. Keywords: dermatopathology, immunocytochemistry, melanocytic lesions, melanocytic neoplasms De la Garza Bravo MM, Curry JL, Torres-Cabala CA, Ivan DS, Drucker C, Prieto VG, Tetzlaff MT. Pigmented extramammary Paget disease of the thigh mimicking a melanocytic tumor: report of a case and review of the literature. J Cutan Pathol 2014; 41: 529–535. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Mammary Paget disease (MPD) was first described in 1874 by Sir James Paget.1 – 4 In approximately 95% of the cases, it represents an intraductal extension of underlying breast carcinoma cells into the epidermis
Maria M. De la Garza Bravo1 , Jonathan L. Curry2,3 , Carlos A. Torres-Cabala2,3 , Doina S. Ivan2,3 , Carol Drucker3 , Victor G. Prieto2,3 and Michael T. Tetzlaff2 1
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA, 2 Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, and 3 Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael T. Tetzlaff Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Unit 85, Houston, TX 77030, USA Tel: 713-792-2585 Fax: 713-745-0778 e-mail: [email protected] Accepted for publication February 21, 2014
of the nipple and areola through the main lactiferous ducts. MPD is rare and occurs in only 1–5% of all mammary carcinomas. MPD can also be due to direct invasion of the epidermis by a subjacent
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De la Garza Bravo et al. infiltrating carcinoma.5 – 7 It has been previously suggested that in the absence of an underlying mammary ductal carcinoma, MPD originates from an intraepidermal glandular cell, the Toker cell.5 – 10 Extramammary Paget disease (EMPD) was first described by Crocker in 1889.11 EMPD is also a rare condition, most commonly affecting patients in their 6–8 decades of life and typically presenting as multifocal, well-circumscribed, pruritic, erythematous plaques or macules12 – 15 in apocrinerich skin, including the vulva, scrotum, axillae, groin and perianal region.13,14 Clinically, EMPD mimics seborrheic dermatitis, Bowen’s disease, psoriasis, intertrigo, eczema or tinea.3,14 – 18 The vulva is the most common location for EMPD in women followed by the perianal region.15 EMPD rarely presents on the abdomen, thigh or face and even more uncommonly presents as a pigmented lesion.14,15 Pigmented EMPD was first described clinically by Cuberson and Horn19 and represents an exceedingly rare lesion: only 10 well-documented cases have been reported so far in the literature,1,6,12,14,15,20,21 although this low number likely represents underreporting of the lesion. Pigmented EMPD presents as an irregular, diffusely pigmented plaque or macule, which clinically can mimic a melanocytic lesion.1,6,12,14,15,20,21 Histopathologically, pigmented EMPD resembles other forms of MPD and EMPD, except the intraepidermal tumor cells typically contain varying amounts of finely granular intracytoplasmic melanin pigment, and there are usually melanophages in the subjacent superficial dermis.5,15 Here, we present an unusual case of pigmented EMPD arising on the thigh of a 51year-old female and summarize the literature on pigmented EMPD. Case report A 51-year-old female with a history of invasive ductal carcinoma 3 years prior presented with a 3 × 6 mm irregularly pigmented brown patch on the right thigh, which she described had been slowly enlarging over the past 6 months. Dermatoscopic evaluation by an experienced dermatologist revealed an asymmetric and irregular pigment network. The clinical impression was that of an atypical melanocytic nevus. Examination of the shave biopsy specimen revealed a disorganized intraepidermal proliferation of single and nested epithelioid cells with pagetoid migration, involving the full thickness of the suprabasal epidermis (Fig. 1A-B). The tumor cells exhibited conspicuous cytologic atypia, including abundant cytoplasm containing prominent fine brown melanin pigment and enlarged, irregular pleomorphic nuclei with occasionally conspicuous
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nucleoli (Fig. 1B). Dermal invasion was not identified. Immunohistochemical studies showed that the tumor cells were strongly and diffusely positive for cytokeratin 7 (Fig. 1C), cytokeratin 8/18 (Fig. 1D) and p63 (Fig. 1H); the tumor cells exhibited variable, weak positivity for epithelial membrane antigen (Fig. 1G). The tumor cells were negative with special studies for intracytoplasmic mucin (data not shown), and for immuno-antibodies for cytokeratin Cam5.2 (Fig. 1F; strongly highlighted scattered intraepidermal Merkel cells), cytokeratin 5/6 (Fig. 1E; highlights surrounding keratinocytes), carcinoembryonic antigen (data not shown), an anti-melanocytic cocktail containing anti-human melanoma black 45 (HMB-45) and anti-tyrosinase (Fig. 1I), and Sox-10 (Fig. 1J). Together with the morphology, these features supported the diagnosis of pigmented EMPD. The patient underwent subsequent wide local excision with 5 mm clinical margins followed by Mohs-assisted excision on the surrounding tissue. Persistent EMPD was not identified in either the central Mohs-debulking specimen (examined in permanent sections) or the peripheral margins (examined by frozen section). Two months after the resection, the patient began a 30-day course of topical imiquimod therapy (5% Aldara applied to the area 5 days/week). An extensive gynecologic and gastroenterologic work-up revealed no underlying carcinoma. The patient is currently free of disease without evidence of local recurrence after 24 months of follow-up. Discussion EMPD is a rare disease that typically presents as an erythematous patch in apocrine-rich skin such as vulva, scrotum, groin, perineum and axillae.1,5,14,21,22 Two types of EMPD are recognized. Type 1 (a.k.a. primary type) includes the vast majority of the cases and is thought to arise as epidermal colonization from transformed cells of underlying cutaneous apocrine glands. Type 1 EMPD is therefore not associated with underlying visceral malignancies.6,22 In type 2 (a.k.a. secondary type), the tumor cells arise as either a direct extension or epidermotropic metastasis from a visceral carcinoma.6,15 Histopathologically, EMPD consists of a disorganized intraepidermal proliferation of malignant epithelioid cells involving the full thickness of the suprabasal epidermis; invasion of the subjacent dermis can occasionally be seen. The tumor cells in EMPD typically stain positively for periodic acid-Schiff (diastase resistant), mucicarmine, aldehyde fuchsin and/or Alcian blue.3,15,22 Immunohistochemically, the tumor cells exhibit positivity for epithelial markers, including cytokeratin 7,
Pigmented Paget disease
Fig. 1. Pigmented extramammary Paget disease. A) Intraepidermal proliferation of single and nested atypical epithelioid cells with increased cytoplasm containing granular brown pigment and enlarged, oval-irregular nuclei (hematoxylin/eosin, ×100). B) Higher magnification shows tumor cells with increased clear cytoplasm with conspicuous brown melanin pigment (hematoxylin/eosin, ×400). Immunohistochemical studies demonstrate that the tumor cells are positive for (C) cytokeratin 7 (CK7), and (D) CK8/18. The tumor cells are negative for CK5/6 (E) and Cam5.2 (F; strongly highlighted scattered intraepidermal Merkel cells and intracytoplasmic melanin pigment is present). The tumor cells exhibit focal positivity for epithelial membrane antigen (EMA; G) and are positive for p63 (H). The tumor cells lack reactivity with a melanocytic cocktail containing antibodies for both human melanoma black 45 (HMB-45) and tyrosinase (I). The tumor cells are also negative for SOX-10 (J). All immunohistochemical studies are displayed at ×200 magnification.
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De la Garza Bravo et al. Table 1. Summary of immunohistochemical features of mammary and extramammary Paget disease and their mimickers
MPD EMPD SCCIS SCC, NOS (including pagetoid SCC) SSM
CK7+ cases/ total (%)
Cam5.2+ cases/ total (%)
Ber-EP4+ cases/ total (%)
p63+ cases/ total (%)
HMB-45+ cases/ total (%)
S100+ cases/ total (%)
101/102 (99) 100/102 (98) 8/73 (11) 24/77 (31)
38/39 (97) 60/60 (100) 4/37 (11) 10/50 (20)
5/9 (56) 38/40 (95) 1/18 (6) 1/50 (2)
NA 8/85 (9)* 31/31 (100) NA
0/42 (0) 0/5 (0) 0/13 (0) NA
12/20 (60) 0/5 (0) 0/1 (0) NA
0/4 (0)
0/4 (0)
NA
NA
20/20 (100)
10/10 (100)
References 8,9,25,29,30,32,34 – 36 8,9,23,24,26 – 28,30,32,34 – 37,39 25,26,28,30,33 – 35 28,31
30,32,34
EMPD, extramammary Paget disease; MPD, mammary Paget disease; NA, not available/not reported; SCCIS, squamous cell carcinoma in situ ; SSM, superficial spreading melanoma. *Includes one case of secondary EMPD
low-molecular weight cytokeratins (with Cam5.2), epithelial membrane antigen (EMA), carcinoembryonic antigen and gross cystic disease fluid protein 15.3,14,15,21 – 24 Anti-cytokeratin 7 has the highest sensitivity and specificity; however, rare cases have been reported to lack cytokeratin 7 expression in tumor cells.9 To distinguish EMPD from ‘pagetoid’ squamous cell carcinoma in situ (SCCIS), traditional markers have included cytokeratin 7 (CK7), Cam5.2, EMA and carcinoembryonic antigen – all of which are generally positive in EMPD and negative in SCCIS. Among these, EMPD is reported to exhibit diffuse and strong positivity for CK7 and Cam5.2. The results of the studies reviewed from the literature are summarized in Table 1.8,9,23 – 37 In approximately 100% of the cases studied, CK7 and Cam5.2 were positive in MPD and EMPD, although rare cases have been reported to be negative for either CK7 or Cam5.2, including the current case which was negative for Cam 5.2 (albeit positive for CK8/18).9,29 In contrast, SCCIS exhibited either CK7-positivity or Cam5.2-positivity in only ∼11% of cases, respectively. However, the percentage of CK7 and Cam5.2-positive cases increased in invasive SCC, particularly lesions that were poorly differentiated or exhibited pagetoid morphology (Table 1).28,31,33 Notably, in the invasive lesions analyzed, the overlying SCCIS component in one study was negative for CK7,31 whereas other studies have shown CK7-positivity in SCCIS associated with invasive SCC.28 Additional markers, including Ber-EP4 and p63, have been proffered to further refine this distinction for those challenging cases where markers like CK7 and Cam5.2 might lack specificity. Moderate to strong Ber-EP4-positivity was detected in approximately 95% cases of EMPD, whereas most cases of SCCIS (94%) were Ber-EP4-negative.34,35 Furthermore, only 2% of invasive SCC was Ber-EP4-positive (Table 1).28 p63 has also emerged as a useful marker
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to distinguish SCCIS from EMPD. Approximately 9% of EMPD cases analyzed were positive for p63 with most of the cases exhibiting weaker staining in the tumor nuclei compared to that seen in the surrounding keratinocyte nuclei.26,27 In contrast, p63 was strongly and diffusely positive in the tumor cells of 100% of SCCIS.26 However, important exceptions to the utility of p63 have been described. Yanai et al. demonstrated p63-positivity in the tumor cells in a case of secondary EMPD arising from an underlying urothelial carcinoma.37 Additionally, Sawada et al. described a case of ‘ectopic’ (i.e. arising in a non-apocrine site) EMPD arising on the back of a 62-year-old Japanese man in which the tumor cells exhibited strong p63-positivity.39 Together with our findings, these cases underscore important possible pitfalls in the specificity of p63 namely, that p63positivity does not necessarily exclude the diagnosis of EMPD – particularly when the lesion arises in non-apocrine locations or in association with underlying malignancy known to express p63.37,39 Future studies to assess the specificity of p63 in ‘ectopic’ EMPD are warranted to further evaluate its utility in that context. In our practice, we typically use variable combinations of Cam5.2, CK7 and p63 to distinguish SCCIS from EMPD, although the current case required additional immunohistochemical work-up to confirm the diagnosis (see below). The diagnosis of EMPD (in particular, the pigmented variant) also relies on the exclusion of melanocytic differentiation: the tumor cells should lack reactivity for melanocytic markers, including S100, MART-1, microphthalmia-associated transcription factor (MiTF) and HMB-45 antigen. In contrast, melanocytic proliferations are reactive for S100 protein, HMB-45 antigen, Melan-A, Sox-10, MiTF and/or MART-1, and very rarely express epithelial markers.1,3,6,7,18,22,29,32 In a systematic study of 20 cases of MPD, 5 cases of EMPD and 10 cases of
Pigmented Paget disease superficial spreading melanomas (SSM), Ramachandra et al. demonstrated HMB-45-positivity in 10/10 SSM, and negativity in 20/20 MPD and 5/5 EMPD (Table 1). Furthermore, all cases of SSM exhibited strong S100-positivity whereas all cases of EMPD were S100-negative.32 However, 60% of their MPD cases (12/20) showed S100-positivity, consistent with previous reports showing S100-positivity in the tumor cells of MPD in up to 10–15% of cases. These observations underscore the need to deploy at least two melanocytic markers in the panel to formally exclude melanocytic differentiation by the tumor cells.1,14,21,32 In rare cases, EMPD presents clinically as a hyperpigmented and/or hypopigmented lesion and is therefore confused clinically (as well as histopathologically) with melanocytic lesions.18 Here, we report a particularly challenging case of pigmented EMPD with several notable possible pitfalls. First, after evaluation by a dermatologist with longstanding experience in dermoscopy, the lesion was thought clinically to represent an atypical melanocytic nevus, arising also on a non-apocrine anatomic location (thigh) unusual for EMPD. Second, histopathologic evaluation revealed a proliferation of atypical epithelioid cells with conspicuous intracytoplasmic pigment, possibly further re-enforcing the possibility of misdiagnosis as a pigmented lesion. Finally, the tumor cells strongly expressed p63 and lacked expression of Cam5.2 – unusual findings in EMPD. Nevertheless, additional diagnostic workup showed the tumor cells to strongly express CK8/18 and CK7, while lacking reactivity for CK5/6 as well as melanocytic markers (HMB45, tyrosinase and Sox-10), which taken together with the clinical history, confirmed the diagnosis of pigmented EMPD. To the best of our knowledge, only 11 cases of pigmented EMPD (including the current case) have been described in the literature to date (Table 2).1,6,12,14,15,20,21 We searched for cases with the following parameters: (a) pathological diagnosis of pigmented EMPD; (b) presence of hyperpigmentation by dermatoscopy and/or histopathology; (c) immunohistochemical studies that distinguish EMPD [e.g. CK7, carcinoembryonic antigen (CEA), EMA and gross cystic disease fluid protein 15 (GCDFP15)] from melanocytic lesions (e.g. S100, Melan-A, MiTF, HMB-45, etc.); (d) tumor characteristics, including location and clinical presentation; and (e) presence or absence of an underlying adenocarcinoma. Five cases occurred in males (45%) with an average age of 72 years; and six cases developed in females (55%) with an average age of 57 years (Table 2).1,6,12,14,15,20,21 Thus, in contrast
to MPD and EMPD which occur predominantly in females, pigmented EMPD apparently exhibits an equal sex distribution. However, pigmented EMPD presents in females at an earlier average age than in males. Similar to MPD and EMPD, the vulva and scrotum (three cases each) were the most common anatomic sites involved by pigmented EMPD, followed by the axilla (two cases). However, the case reported by Vincent et al. (abdomen) and our current case (right thigh) presented in non-apocrine skin (18%), making the recognition of pigmented EMPD in these non-canonical sites even more challenging.14 There is a variable association with internal malignancy reported for EMPD.3,6,13,14,18,22,38,39 Consistent with this, only 4 of the 11 cases of pigmented EMPD (4/11; ∼36%) were associated with an internal malignancy, and this relationship appeared tenuous. One case showed some anatomic proximity (pigmented EMPD on the abdomen of a 63-year-old female) to the underlying carcinoma (colonic adenocarcinoma).14 However, in the remaining three cases, there was an apparent disconnect between the site of pigmented EMPD and the anatomic location of the internal malignancy (Table 2). For 3 of the 11 cases (including the current case), information regarding treatment and follow up was available. Each of these three cases was treated with wide local excision with negative margins and an average disease-free interval of 15 months (9–24 months follow-up).1,14 Histopathologically, all cases of pigmented EMPD resemble typical EMPD (i.e. an intraepidermal proliferation of atypical epithelioid cells with abundant cytoplasm and enlarged nuclei with prominent nucleoli). However, pigmented EMPD is characterized either by conspicuous intracytoplasmic melanin pigment in the tumor cells (described in 9/11 cases) or by increased dendritic melanocytes scattered among the tumor cells (described in 2/11 cases).1,6,12,14,15,20,21 Moreover, one case also presented with increased melanophages in the subjacent dermis.1,12 Given these various histopathologic observations, three possible mechanisms have been proposed to explain the pathogenesis of increased pigmentation observed in pigmented EMPD: (a) melanocytic colonization mediated by tumor cell-produced factors such as basic fibroblast growth factor (bFGF), melanocytestimulating hormone, epidermal growth factor, insulin and stem cell factor; (2) increased melanin pigment production by the surrounding melanocytes and transfer to the tumor cells; and/or (3) increased melanophages in the subjacent dermis.20 In summary, pigmented EMPD is a rare disease that can present as a pigmented lesion anywhere on the body. Immunohistochemical stains are helpful in recognizing this entity among melanocytic lesions.
533
534 Vulva Scrotum Scrotum Abdomen
43/F 58/M 63/M 63/F 83/M
76/M 51/F
Petersson et al. (2009)6
Vincent et al. (2011)14
Coras-Stepanek et al. (2012)20
Wang et al. (2012)15
This study (2014)
Pigmented patch
Erythematous plaque with depigmentation with sharp partly hyperpigmented margin Irregular hyperpigmented macule Variegated brown plaque
Erythematous and black-brown patch NA NA Pigmented lesion
Brown-black macule Erythematous plaque; focally pigmented Red-brown roughened area Pigmented plaque
Clinical presentation
Breast adenocarcinoma
Prostatic adenocarcinoma
NA
NA
No No Colonic adenocarcinoma
No
No No
Breast adenocarcinoma NA
Other malignancies
CK7, CK8/18, and EMA
CK7 and CEA
CK7, CEA
NA
CK7, CEA, GCDFP-15 Cam5.2, EMA, CEA CK7
CEA Pan-CK, CK7, Cam5.2, EMA and CEA. GCDFP15 and mucicarmine (weakly) CK7
Cam5.2, CEA Cam5.2, CEA
Positive
CK20, S100, Melan-A and HMB-45 CK20, CK34βE12, S100, Melan-A, and HMB-45 Cam5.2, CEA, HMB-45, tyrosinase and MITF
CK20, S100, MITF, Melan-A, and HMB-45 NA
Mart-1 and HMB-45 CK34βE12, CK20, S100, Mart-1, HMB-45 and MITF CEA, HMB-45, Melan-A and S100 CK20
HMB-45 and S100 HMB-45 and S100
Negative
Immunohistochemistry of tumor cells
CEA, carcinoembryonic antigen; CK, cytokeratin; CK34βE12, cytokeratin 34 beta E12; CK7, cytokeratin 7; CK20, cytokeratin 20; EMA, epithelial membrane antigen, F, female; GCDFP15, gross cystic disease fluid protein 15; HMB-45, human melanoma black 45; IHC, immunohistochemistry; M, male; MITF, microphthalmia-associated transcription factor; NA, not available/not reported; yr, years.
Thigh
Axilla
Scrotum
Groin
Perineum Axilla
63/F 79/M
Gumurdula et al. (2004)21 Hilliard et al. (2009)1
Vulva Vulva
Site
52/F 70/F
Age (yr)/gender
Chiba et al. (2000)12
Author (year), reference
Table 2. Summary of pigmented extramammary Paget disease reported in the literature to date
De la Garza Bravo et al.
Pigmented Paget disease Here, we present a case of pigmented EMPD arising in non-apocrine skin to highlight this entity as an important pitfall in the distinction from melanocytic tumors, including Spitz nevi and/or melanoma in situ.
Acknowledgement The authors would like to thank Ms. Kim-Anh Vu for her excellent assistance in assembling the figure.
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