What Is This Erythematous Infiltrative Plaque In The Groin?

Diagnosis: Extramammary Paget Disease 

In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease (MPD). In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Differences between the 2 entities include anatomic location, pathogenesis, and epidemiology.^1,2 

EMPD is a rare apocrine adenocarcinoma representing about 6.5% of all cutaneous Paget disease.^3,4 Typically, EMPD is found in the epidermis where apocrine glands exist (ie, perineum, groin, and axillae), but holds the potential to invade the adnexa and dermis.^2,3 EMPD may also occur in nonapocrine gland bearing areas (ie, chest, arms, fingers, knee, back, and cheeks), in which case it is termed ectopic EMPD.^5-7 This entity is scarcely described in the literature and other than its location, is identical to EMPD with respect to presentation, histology, management, and prognosis.⁵ 

Patients most commonly presenting with EMPD in general are white, female, and middle-aged (aged 45 to 85). However, this does differ between races as there is a male predominance in Asian populations.^8,9 Female-to-male ratio was found to be 1:1.3 in one study.¹⁰ Familial cases are rare, but several have been reported in the literature.⁹

Clinical Presentation

Primary EMPD originates in the skin and represents the majority of the cases. The cause of primary EMPD is unknown.¹¹ Alternatively, secondary EMPD comprises 25% of cases and is associated with an underlying adenocarcinoma originating in the rectum, vagina, prostate, cervix, urethra, or bladder.^3,6 Additionally, EMPD can be focal (ie, only one apocrine gland bearing area) or multifocal (ie, groin and axillae).⁴ Aside from skin, Paget disease can be found in the breast, bone, and nonapocrine gland bearing areas. Table 1 further clarifies the different types of EMPD. 

EMPD often presents as an indolent, well-demarcated, erythematous, or eczematous patch or plaque with a scaly or ulcerated surface (Figure). Some reports also indicate that EMPD may present as a white or pigmented lesion.² Lesions often measure 1 to several centimeters in diameter. Additionally, hard nodules or regional lymph node enlargement may subsequently develop. The most common symptom associated with EMPD is pruritus.⁹ Other associated symptoms include burning, pain, tenderness, edema, and hyperpigmentation or hypopigmentation.³ Asymptomatic cases do exist, but occur only in a small percentage of cases.⁸ 

The most common location of EMPD is around the vulva, accounting for nearly 50% to 65% of cases, followed by the perineum (area between the anus and scrotum or vulva), perianal region, scrotum, and penis. Less commonly, it can appear in the axilla, buttocks, thighs, eyelids, external auditory canal, and other skin or mucosal surfaces with apocrine glands.^6,7,9

Histopathology

Histopathologic findings of EMPD and Paget disease are very similar. The characteristic neoplastic cells, or “Paget cells”, are described as large and round with abundant, finely granular basophilic or amphophilic cytoplasm and large, centrally located nuclei with prominent nucleoli.^6,12 These Paget cells may be dispersed individually within the lower epidermis (less commonly in the upper epidermis), or form glandular structures or solid nests. Additionally, they may be found within the dermis or adnexa if invasion occurred. A dense dermal inflammatory infiltrate may also be seen in association with the Paget cells.^9,12 

Immunohistochemical staining is also useful to evaluate surgical margins or differentiate EMPD from alternative diagnoses such as malignant melanoma. Classically, EMPD stains positive for glandular cytokeratin (CK), specifically CK7 or CK20. CK20, however, is more likely to indicate secondary EMPD than CK7.⁹ Other positively associated immunohistochemical stains for EMPD include periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 (GCDFP-15), epithelial membrane antigen, and aldehyde fuchsin.¹² Alternatively, S100 expression would not exist in cases of EMPD allowing for differentiation from alternative diagnoses like melanoma.^3,6,9,12 Immunohistochemical stains may also suggest presence of an underlying malignancy in cases of perianal and vulvar EMPD where CK20⁺/GCDFP-15^- is more associated with underlying malignancies compared to CK20^-/GCDFP-15⁺.⁹ 

Comparatively, EMPD and MPD both stain positive for CK7, CK20, and CEA. However, CK20 is more specific for EMPD where as CK7 has good sensitivity for both EMPD and MPD.⁹ Additionally, EMPD stains positive for PAS as it has mucin-containing tumor cells, whereas MPD does not. On the other hand, about 50% of MPD cases are progesterone and estrogen receptor positive, whereas tumor cells in EMPD will not be positive for these two receptors.⁴ Also, HER2 overexpression is more frequently found in MPD than in cases of EMPD, allowing for further differentiation between the two entities⁹ (Table 1).

Pathogenesis

EMPD can develop as an intraepithelial neoplasm from epidermal basal cells or arise secondary to an underlying carcinoma by epidermotropic spread of malignant adenocarcinoma cells.⁹ When associated with an underlying malignancy, anatomic location appears to play a role. For example, genital (ie, penis or vulva) disease is associated with carcinoma in about 4% to 7% of patients, while perianal disease is associated with underlying colorectal carcinoma in 25% to 35% of cases.^3,11 However, cases of MPD are more likely to be associated with malignancy than cases of EMPD.¹²

The exact origin and pathogenesis of EMPD or ectopic variants is unclear, however, several speculations exist. To date, Paget cells have been associated with apocrine and eccrine glands, epidermal pluripotent keratinocyte stem cells, and more recently, Toker cells. Toker cells are present in both mammary and vulvar tissue.^9,13 They are primitive cells of lactiferous ducts and hypothesized as the precursor of EMPD; however, they are not found in genital skin (penis, anus, scrotum), aside from the vulva, where EMPD is most commonly found.¹³ 

Differential Diagnosis

EMPD often mimics benign inflammatory dermatological conditions. Because of this, an accurate diagnosis can be delayed by months to years until subsequent incisional biopsy confirms the presence of the disease.¹⁴ The clinical differential diagnosis for EMPD includes eczema, contact dermatitis, intertrigo, dermatophytoses, psoriasis, lichen sclerosis, Bowen’s disease, superficial basal cell carcinoma, melanoma, and mycosis fungoides.^8,12

EMPD may also be associated with an underlying adenocarcinoma (secondary EMPD). A detailed review of systems and physical examination should be performed if EMPD is suspected. The examination should include a full skin examination, palpation of all lymph nodes, and a rectal examination. Endoscopic or imaging studies should be considered at the time of diagnosis to assess possible undetected internal malignancy. In women, pelvic examinations, Pap test, breast examinations, and colposcopy may also be helpful.^11,15

Management

The most common therapeutic approaches for EMPD include surgical excision, Mohs micrographic surgery (MMS), and topical chemotherapy (Table 2). Surgical excision is the standard of care at this time. Ideal surgical margins are stated to range from 1 to 3 cm.¹⁶ However, it is difficult to distinguish microscopic extension of EMPD beyond clinical margins, leading to higher reoccurrence rates and repeated surgeries.¹⁶ Additionally, several studies have reported that MMS may be a better approach with lower recurrence rates.^8,17-19 This is because of the ability to microscopically visualize tumor margins using frozen sections, ultimately reducing recurrence rates and morbidity and mortality.²⁰ For primary tumors, the recurrence rate after surgical excision is about 20% to 60%.¹⁶ With MMS the recurrence rate is about 8% to 26%. The average time to recurrence following surgery is 2.5 years.¹¹ Unfortunately, efficacy of MMS for EMPD is controversial due to rarity of the disease, lack of controlled trials, small sample sizes, and publication bias.¹⁶

Chemotherapeutic agents are used as an alternative when surgery is contraindicated. A small number of patients have been successfully treated with 5-fluorouracil,²¹ imiquimod,²² and a combination of paclitaxel and trastuzumab.²³ For example, imiquimod 5% cream applied 3 times a week for 16 weeks induced complete resolution in a patient with perineal EMPD.²² Similarly, another study of 21 women with EMPD of the vulva treated with imiquimod 5% cream found an 81% response rate.²⁴ Further research with larger sample sizes are needed to confirm the use of topical chemotherapy for patients with EMPD.²⁵

Other forms of treatment for EMPD, alone or in combination, include photodynamic therapy, external beam radiotherapy, brachytherapy, and laser therapy.^19,26 Coordination with an appropriate surgical subspecialist (eg, a urologist or gynecologist) with experience treating the condition may be needed on a case by case basis.¹¹

Prognosis

EMPD, when confined to the epidermis, has an excellent prognosis with a generalized 5-year survival rate of 72%.⁴ The challenge for these patients is symptom management and the early detection and treatment of local recurrence. Alternatively, invasive primary EMPD has a poor prognosis if dermal invasion is >1 mm.^9,19,27 

Morbidity and mortality are increased when tumor cells infiltrate the dermis, adnexa, or lymph nodes.²⁸ In such cases, extensive surgical treatment or chemotherapy may be associated with a poor prognosis. Some studies also demonstrate higher mortality rates among patients with an associated carcinoma.¹¹ 

Our Patient

Prior to presentation to our clinic, the patient was treated with fluconazole, mometasone, ketoconazole, and Domeboro soaks without improvement. Two weeks later, a shave biopsy of the right inner thigh was performed. This confirmed EMPD with no dermal involvement. Sections of skin showed large epithelioid tumorous cells dispersed as single and variably sized clusters throughout the mildly thickened epidermis. These cells were round to ovoid with abundant pale to amphophilic cytoplasm and expressed carcinoembryonic antigen, epithelial membrane antigen, AE1/AE3, and P63. There was no expression of Melan-A or S100 protein in the cells. The patient was referred for extension and association workup and management in a multidisciplinary clinic with an oncologist and general surgeon. 

Conclusion

EMPD often presents as an indolent, well-demarcated, erythematous, or eczematous patch or plaque with a scaly or ulcerated surface that is often mistaken for benign inflammatory dermatologic conditions. An accurate diagnosis can be delayed by months to years until biopsy confirms the presence of the disease. Skin biopsies should be performed in patients with pruritic eczematous lesions of apocrine gland bearing areas that fail to respond within 4 to 6 weeks of standard topical treatment.¹⁹ Recommended therapeutic approaches for EMPD include MMS and wide surgical excision. Topical chemotherapy and other forms of treatment should be considered when surgery is contraindicated.

This case highlights the complexity of EMPD and the difficulty that comes in diagnosing and treating the condition. 

Ms Arthur is with Michigan State University College of Human Medicine in East Lansing, MI.

Dr Ashack is with Michigan State University College of Human Medicine in East Lansing, MI, and also with the department of dermatology at the University of Illinois at Chicago, in Chicago, IL.

Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Diagnosis: Extramammary Paget Disease 

In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease (MPD). In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Differences between the 2 entities include anatomic location, pathogenesis, and epidemiology.^1,2 

EMPD is a rare apocrine adenocarcinoma representing about 6.5% of all cutaneous Paget disease.^3,4 Typically, EMPD is found in the epidermis where apocrine glands exist (ie, perineum, groin, and axillae), but holds the potential to invade the adnexa and dermis.^2,3 EMPD may also occur in nonapocrine gland bearing areas (ie, chest, arms, fingers, knee, back, and cheeks), in which case it is termed ectopic EMPD.^5-7 This entity is scarcely described in the literature and other than its location, is identical to EMPD with respect to presentation, histology, management, and prognosis.⁵ 

Patients most commonly presenting with EMPD in general are white, female, and middle-aged (aged 45 to 85). However, this does differ between races as there is a male predominance in Asian populations.^8,9 Female-to-male ratio was found to be 1:1.3 in one study.¹⁰ Familial cases are rare, but several have been reported in the literature.⁹

Clinical Presentation

Primary EMPD originates in the skin and represents the majority of the cases. The cause of primary EMPD is unknown.¹¹ Alternatively, secondary EMPD comprises 25% of cases and is associated with an underlying adenocarcinoma originating in the rectum, vagina, prostate, cervix, urethra, or bladder.^3,6 Additionally, EMPD can be focal (ie, only one apocrine gland bearing area) or multifocal (ie, groin and axillae).⁴ Aside from skin, Paget disease can be found in the breast, bone, and nonapocrine gland bearing areas. Table 1 further clarifies the different types of EMPD. 

EMPD often presents as an indolent, well-demarcated, erythematous, or eczematous patch or plaque with a scaly or ulcerated surface (Figure). Some reports also indicate that EMPD may present as a white or pigmented lesion.² Lesions often measure 1 to several centimeters in diameter. Additionally, hard nodules or regional lymph node enlargement may subsequently develop. The most common symptom associated with EMPD is pruritus.⁹ Other associated symptoms include burning, pain, tenderness, edema, and hyperpigmentation or hypopigmentation.³ Asymptomatic cases do exist, but occur only in a small percentage of cases.⁸ 

The most common location of EMPD is around the vulva, accounting for nearly 50% to 65% of cases, followed by the perineum (area between the anus and scrotum or vulva), perianal region, scrotum, and penis. Less commonly, it can appear in the axilla, buttocks, thighs, eyelids, external auditory canal, and other skin or mucosal surfaces with apocrine glands.^6,7,9

Histopathology

Histopathologic findings of EMPD and Paget disease are very similar. The characteristic neoplastic cells, or “Paget cells”, are described as large and round with abundant, finely granular basophilic or amphophilic cytoplasm and large, centrally located nuclei with prominent nucleoli.^6,12 These Paget cells may be dispersed individually within the lower epidermis (less commonly in the upper epidermis), or form glandular structures or solid nests. Additionally, they may be found within the dermis or adnexa if invasion occurred. A dense dermal inflammatory infiltrate may also be seen in association with the Paget cells.^9,12 

Immunohistochemical staining is also useful to evaluate surgical margins or differentiate EMPD from alternative diagnoses such as malignant melanoma. Classically, EMPD stains positive for glandular cytokeratin (CK), specifically CK7 or CK20. CK20, however, is more likely to indicate secondary EMPD than CK7.⁹ Other positively associated immunohistochemical stains for EMPD include periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 (GCDFP-15), epithelial membrane antigen, and aldehyde fuchsin.¹² Alternatively, S100 expression would not exist in cases of EMPD allowing for differentiation from alternative diagnoses like melanoma.^3,6,9,12 Immunohistochemical stains may also suggest presence of an underlying malignancy in cases of perianal and vulvar EMPD where CK20⁺/GCDFP-15^- is more associated with underlying malignancies compared to CK20^-/GCDFP-15⁺.⁹ 

Comparatively, EMPD and MPD both stain positive for CK7, CK20, and CEA. However, CK20 is more specific for EMPD where as CK7 has good sensitivity for both EMPD and MPD.⁹ Additionally, EMPD stains positive for PAS as it has mucin-containing tumor cells, whereas MPD does not. On the other hand, about 50% of MPD cases are progesterone and estrogen receptor positive, whereas tumor cells in EMPD will not be positive for these two receptors.⁴ Also, HER2 overexpression is more frequently found in MPD than in cases of EMPD, allowing for further differentiation between the two entities⁹ (Table 1).

Pathogenesis

EMPD can develop as an intraepithelial neoplasm from epidermal basal cells or arise secondary to an underlying carcinoma by epidermotropic spread of malignant adenocarcinoma cells.⁹ When associated with an underlying malignancy, anatomic location appears to play a role. For example, genital (ie, penis or vulva) disease is associated with carcinoma in about 4% to 7% of patients, while perianal disease is associated with underlying colorectal carcinoma in 25% to 35% of cases.^3,11 However, cases of MPD are more likely to be associated with malignancy than cases of EMPD.¹²

The exact origin and pathogenesis of EMPD or ectopic variants is unclear, however, several speculations exist. To date, Paget cells have been associated with apocrine and eccrine glands, epidermal pluripotent keratinocyte stem cells, and more recently, Toker cells. Toker cells are present in both mammary and vulvar tissue.^9,13 They are primitive cells of lactiferous ducts and hypothesized as the precursor of EMPD; however, they are not found in genital skin (penis, anus, scrotum), aside from the vulva, where EMPD is most commonly found.¹³ 

Differential Diagnosis

EMPD often mimics benign inflammatory dermatological conditions. Because of this, an accurate diagnosis can be delayed by months to years until subsequent incisional biopsy confirms the presence of the disease.¹⁴ The clinical differential diagnosis for EMPD includes eczema, contact dermatitis, intertrigo, dermatophytoses, psoriasis, lichen sclerosis, Bowen’s disease, superficial basal cell carcinoma, melanoma, and mycosis fungoides.^8,12

EMPD may also be associated with an underlying adenocarcinoma (secondary EMPD). A detailed review of systems and physical examination should be performed if EMPD is suspected. The examination should include a full skin examination, palpation of all lymph nodes, and a rectal examination. Endoscopic or imaging studies should be considered at the time of diagnosis to assess possible undetected internal malignancy. In women, pelvic examinations, Pap test, breast examinations, and colposcopy may also be helpful.^11,15

Management

The most common therapeutic approaches for EMPD include surgical excision, Mohs micrographic surgery (MMS), and topical chemotherapy (Table 2). Surgical excision is the standard of care at this time. Ideal surgical margins are stated to range from 1 to 3 cm.¹⁶ However, it is difficult to distinguish microscopic extension of EMPD beyond clinical margins, leading to higher reoccurrence rates and repeated surgeries.¹⁶ Additionally, several studies have reported that MMS may be a better approach with lower recurrence rates.^8,17-19 This is because of the ability to microscopically visualize tumor margins using frozen sections, ultimately reducing recurrence rates and morbidity and mortality.²⁰ For primary tumors, the recurrence rate after surgical excision is about 20% to 60%.¹⁶ With MMS the recurrence rate is about 8% to 26%. The average time to recurrence following surgery is 2.5 years.¹¹ Unfortunately, efficacy of MMS for EMPD is controversial due to rarity of the disease, lack of controlled trials, small sample sizes, and publication bias.¹⁶

Chemotherapeutic agents are used as an alternative when surgery is contraindicated. A small number of patients have been successfully treated with 5-fluorouracil,²¹ imiquimod,²² and a combination of paclitaxel and trastuzumab.²³ For example, imiquimod 5% cream applied 3 times a week for 16 weeks induced complete resolution in a patient with perineal EMPD.²² Similarly, another study of 21 women with EMPD of the vulva treated with imiquimod 5% cream found an 81% response rate.²⁴ Further research with larger sample sizes are needed to confirm the use of topical chemotherapy for patients with EMPD.²⁵

Other forms of treatment for EMPD, alone or in combination, include photodynamic therapy, external beam radiotherapy, brachytherapy, and laser therapy.^19,26 Coordination with an appropriate surgical subspecialist (eg, a urologist or gynecologist) with experience treating the condition may be needed on a case by case basis.¹¹

Prognosis

EMPD, when confined to the epidermis, has an excellent prognosis with a generalized 5-year survival rate of 72%.⁴ The challenge for these patients is symptom management and the early detection and treatment of local recurrence. Alternatively, invasive primary EMPD has a poor prognosis if dermal invasion is >1 mm.^9,19,27 

Morbidity and mortality are increased when tumor cells infiltrate the dermis, adnexa, or lymph nodes.²⁸ In such cases, extensive surgical treatment or chemotherapy may be associated with a poor prognosis. Some studies also demonstrate higher mortality rates among patients with an associated carcinoma.¹¹ 

Our Patient

Prior to presentation to our clinic, the patient was treated with fluconazole, mometasone, ketoconazole, and Domeboro soaks without improvement. Two weeks later, a shave biopsy of the right inner thigh was performed. This confirmed EMPD with no dermal involvement. Sections of skin showed large epithelioid tumorous cells dispersed as single and variably sized clusters throughout the mildly thickened epidermis. These cells were round to ovoid with abundant pale to amphophilic cytoplasm and expressed carcinoembryonic antigen, epithelial membrane antigen, AE1/AE3, and P63. There was no expression of Melan-A or S100 protein in the cells. The patient was referred for extension and association workup and management in a multidisciplinary clinic with an oncologist and general surgeon. 

Conclusion

EMPD often presents as an indolent, well-demarcated, erythematous, or eczematous patch or plaque with a scaly or ulcerated surface that is often mistaken for benign inflammatory dermatologic conditions. An accurate diagnosis can be delayed by months to years until biopsy confirms the presence of the disease. Skin biopsies should be performed in patients with pruritic eczematous lesions of apocrine gland bearing areas that fail to respond within 4 to 6 weeks of standard topical treatment.¹⁹ Recommended therapeutic approaches for EMPD include MMS and wide surgical excision. Topical chemotherapy and other forms of treatment should be considered when surgery is contraindicated.

This case highlights the complexity of EMPD and the difficulty that comes in diagnosing and treating the condition. 

Ms Arthur is with Michigan State University College of Human Medicine in East Lansing, MI.

Dr Ashack is with Michigan State University College of Human Medicine in East Lansing, MI, and also with the department of dermatology at the University of Illinois at Chicago, in Chicago, IL.

Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.

Diagnosis: Extramammary Paget Disease 

In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease (MPD). In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Differences between the 2 entities include anatomic location, pathogenesis, and epidemiology.^1,2 

EMPD is a rare apocrine adenocarcinoma representing about 6.5% of all cutaneous Paget disease.^3,4 Typically, EMPD is found in the epidermis where apocrine glands exist (ie, perineum, groin, and axillae), but holds the potential to invade the adnexa and dermis.^2,3 EMPD may also occur in nonapocrine gland bearing areas (ie, chest, arms, fingers, knee, back, and cheeks), in which case it is termed ectopic EMPD.^5-7 This entity is scarcely described in the literature and other than its location, is identical to EMPD with respect to presentation, histology, management, and prognosis.⁵ 

Patients most commonly presenting with EMPD in general are white, female, and middle-aged (aged 45 to 85). However, this does differ between races as there is a male predominance in Asian populations.^8,9 Female-to-male ratio was found to be 1:1.3 in one study.¹⁰ Familial cases are rare, but several have been reported in the literature.⁹

Clinical Presentation

Primary EMPD originates in the skin and represents the majority of the cases. The cause of primary EMPD is unknown.¹¹ Alternatively, secondary EMPD comprises 25% of cases and is associated with an underlying adenocarcinoma originating in the rectum, vagina, prostate, cervix, urethra, or bladder.^3,6 Additionally, EMPD can be focal (ie, only one apocrine gland bearing area) or multifocal (ie, groin and axillae).⁴ Aside from skin, Paget disease can be found in the breast, bone, and nonapocrine gland bearing areas. Table 1 further clarifies the different types of EMPD. 

EMPD often presents as an indolent, well-demarcated, erythematous, or eczematous patch or plaque with a scaly or ulcerated surface (Figure). Some reports also indicate that EMPD may present as a white or pigmented lesion.² Lesions often measure 1 to several centimeters in diameter. Additionally, hard nodules or regional lymph node enlargement may subsequently develop. The most common symptom associated with EMPD is pruritus.⁹ Other associated symptoms include burning, pain, tenderness, edema, and hyperpigmentation or hypopigmentation.³ Asymptomatic cases do exist, but occur only in a small percentage of cases.⁸ 

The most common location of EMPD is around the vulva, accounting for nearly 50% to 65% of cases, followed by the perineum (area between the anus and scrotum or vulva), perianal region, scrotum, and penis. Less commonly, it can appear in the axilla, buttocks, thighs, eyelids, external auditory canal, and other skin or mucosal surfaces with apocrine glands.^6,7,9

Histopathology

Histopathologic findings of EMPD and Paget disease are very similar. The characteristic neoplastic cells, or “Paget cells”, are described as large and round with abundant, finely granular basophilic or amphophilic cytoplasm and large, centrally located nuclei with prominent nucleoli.^6,12 These Paget cells may be dispersed individually within the lower epidermis (less commonly in the upper epidermis), or form glandular structures or solid nests. Additionally, they may be found within the dermis or adnexa if invasion occurred. A dense dermal inflammatory infiltrate may also be seen in association with the Paget cells.^9,12 

Immunohistochemical staining is also useful to evaluate surgical margins or differentiate EMPD from alternative diagnoses such as malignant melanoma. Classically, EMPD stains positive for glandular cytokeratin (CK), specifically CK7 or CK20. CK20, however, is more likely to indicate secondary EMPD than CK7.⁹ Other positively associated immunohistochemical stains for EMPD include periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 (GCDFP-15), epithelial membrane antigen, and aldehyde fuchsin.¹² Alternatively, S100 expression would not exist in cases of EMPD allowing for differentiation from alternative diagnoses like melanoma.^3,6,9,12 Immunohistochemical stains may also suggest presence of an underlying malignancy in cases of perianal and vulvar EMPD where CK20⁺/GCDFP-15^- is more associated with underlying malignancies compared to CK20^-/GCDFP-15⁺.⁹ 

Comparatively, EMPD and MPD both stain positive for CK7, CK20, and CEA. However, CK20 is more specific for EMPD where as CK7 has good sensitivity for both EMPD and MPD.⁹ Additionally, EMPD stains positive for PAS as it has mucin-containing tumor cells, whereas MPD does not. On the other hand, about 50% of MPD cases are progesterone and estrogen receptor positive, whereas tumor cells in EMPD will not be positive for these two receptors.⁴ Also, HER2 overexpression is more frequently found in MPD than in cases of EMPD, allowing for further differentiation between the two entities⁹ (Table 1).

Pathogenesis

EMPD can develop as an intraepithelial neoplasm from epidermal basal cells or arise secondary to an underlying carcinoma by epidermotropic spread of malignant adenocarcinoma cells.⁹ When associated with an underlying malignancy, anatomic location appears to play a role. For example, genital (ie, penis or vulva) disease is associated with carcinoma in about 4% to 7% of patients, while perianal disease is associated with underlying colorectal carcinoma in 25% to 35% of cases.^3,11 However, cases of MPD are more likely to be associated with malignancy than cases of EMPD.¹²

The exact origin and pathogenesis of EMPD or ectopic variants is unclear, however, several speculations exist. To date, Paget cells have been associated with apocrine and eccrine glands, epidermal pluripotent keratinocyte stem cells, and more recently, Toker cells. Toker cells are present in both mammary and vulvar tissue.^9,13 They are primitive cells of lactiferous ducts and hypothesized as the precursor of EMPD; however, they are not found in genital skin (penis, anus, scrotum), aside from the vulva, where EMPD is most commonly found.¹³ 

Differential Diagnosis

EMPD often mimics benign inflammatory dermatological conditions. Because of this, an accurate diagnosis can be delayed by months to years until subsequent incisional biopsy confirms the presence of the disease.¹⁴ The clinical differential diagnosis for EMPD includes eczema, contact dermatitis, intertrigo, dermatophytoses, psoriasis, lichen sclerosis, Bowen’s disease, superficial basal cell carcinoma, melanoma, and mycosis fungoides.^8,12

EMPD may also be associated with an underlying adenocarcinoma (secondary EMPD). A detailed review of systems and physical examination should be performed if EMPD is suspected. The examination should include a full skin examination, palpation of all lymph nodes, and a rectal examination. Endoscopic or imaging studies should be considered at the time of diagnosis to assess possible undetected internal malignancy. In women, pelvic examinations, Pap test, breast examinations, and colposcopy may also be helpful.^11,15

Management

The most common therapeutic approaches for EMPD include surgical excision, Mohs micrographic surgery (MMS), and topical chemotherapy (Table 2). Surgical excision is the standard of care at this time. Ideal surgical margins are stated to range from 1 to 3 cm.¹⁶ However, it is difficult to distinguish microscopic extension of EMPD beyond clinical margins, leading to higher reoccurrence rates and repeated surgeries.¹⁶ Additionally, several studies have reported that MMS may be a better approach with lower recurrence rates.^8,17-19 This is because of the ability to microscopically visualize tumor margins using frozen sections, ultimately reducing recurrence rates and morbidity and mortality.²⁰ For primary tumors, the recurrence rate after surgical excision is about 20% to 60%.¹⁶ With MMS the recurrence rate is about 8% to 26%. The average time to recurrence following surgery is 2.5 years.¹¹ Unfortunately, efficacy of MMS for EMPD is controversial due to rarity of the disease, lack of controlled trials, small sample sizes, and publication bias.¹⁶

Chemotherapeutic agents are used as an alternative when surgery is contraindicated. A small number of patients have been successfully treated with 5-fluorouracil,²¹ imiquimod,²² and a combination of paclitaxel and trastuzumab.²³ For example, imiquimod 5% cream applied 3 times a week for 16 weeks induced complete resolution in a patient with perineal EMPD.²² Similarly, another study of 21 women with EMPD of the vulva treated with imiquimod 5% cream found an 81% response rate.²⁴ Further research with larger sample sizes are needed to confirm the use of topical chemotherapy for patients with EMPD.²⁵

Other forms of treatment for EMPD, alone or in combination, include photodynamic therapy, external beam radiotherapy, brachytherapy, and laser therapy.^19,26 Coordination with an appropriate surgical subspecialist (eg, a urologist or gynecologist) with experience treating the condition may be needed on a case by case basis.¹¹

Prognosis

EMPD, when confined to the epidermis, has an excellent prognosis with a generalized 5-year survival rate of 72%.⁴ The challenge for these patients is symptom management and the early detection and treatment of local recurrence. Alternatively, invasive primary EMPD has a poor prognosis if dermal invasion is >1 mm.^9,19,27 

Morbidity and mortality are increased when tumor cells infiltrate the dermis, adnexa, or lymph nodes.²⁸ In such cases, extensive surgical treatment or chemotherapy may be associated with a poor prognosis. Some studies also demonstrate higher mortality rates among patients with an associated carcinoma.¹¹ 

Our Patient

Prior to presentation to our clinic, the patient was treated with fluconazole, mometasone, ketoconazole, and Domeboro soaks without improvement. Two weeks later, a shave biopsy of the right inner thigh was performed. This confirmed EMPD with no dermal involvement. Sections of skin showed large epithelioid tumorous cells dispersed as single and variably sized clusters throughout the mildly thickened epidermis. These cells were round to ovoid with abundant pale to amphophilic cytoplasm and expressed carcinoembryonic antigen, epithelial membrane antigen, AE1/AE3, and P63. There was no expression of Melan-A or S100 protein in the cells. The patient was referred for extension and association workup and management in a multidisciplinary clinic with an oncologist and general surgeon. 

Conclusion

EMPD often presents as an indolent, well-demarcated, erythematous, or eczematous patch or plaque with a scaly or ulcerated surface that is often mistaken for benign inflammatory dermatologic conditions. An accurate diagnosis can be delayed by months to years until biopsy confirms the presence of the disease. Skin biopsies should be performed in patients with pruritic eczematous lesions of apocrine gland bearing areas that fail to respond within 4 to 6 weeks of standard topical treatment.¹⁹ Recommended therapeutic approaches for EMPD include MMS and wide surgical excision. Topical chemotherapy and other forms of treatment should be considered when surgery is contraindicated.

This case highlights the complexity of EMPD and the difficulty that comes in diagnosing and treating the condition. 

Ms Arthur is with Michigan State University College of Human Medicine in East Lansing, MI.

Dr Ashack is with Michigan State University College of Human Medicine in East Lansing, MI, and also with the department of dermatology at the University of Illinois at Chicago, in Chicago, IL.

Dr Khachemoune, the Section Editor of Derm DX, is with the department of dermatology at Veteran Affairs Medical Center, and the department of dermatology at the State University of New York Downstate, both in Brooklyn, NY.