Case Presentation A 67-year-old white man presented with a 6-month history of a slowly increasing in size, slightly pruritic, erythematous rash in his right lower abdominal quadrant extending to his inguinal fold and right side of his scrotum. He reported having a similar lesion in his right axilla 7 years earlier that was surgically excised with no clinical evidence of recurrence. Otherwise, he was healthy with no history of systemic diseases. On examination there was an 8-cm by 6-cm erythematous, slightly elevated, papillomatous plaque extending from his right pubic area to the right lateral scrotal wall. No alopecia was noted overlying the plaque. No inguinal lymphadenopathy was appreciated on nodal examination. A well-healed scar was present in the right axilla, but no axillary adenopathy was noted. A KOH preparation of the lesion was negative for hyphae. Histologic examination of a 4-mm punch biopsy specimen taken from the inguinal plaque revealed an atypical cellular proliferation composed of clear cells ascending through the epidermis. These cells were positive for carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA) and mucicarmine stains. The S-100 stain did not stain these cells. What’s Your Diagnosis?
Diagnosis: Extramammary Paget’s Disease
Paget's disease of the breast, also known as mammary Paget’s disease (MPD), was first described by Sir James Paget in 1874.1 Extramammary Paget’s disease (EMPD) was originally described by Crocker in 1889 after he discovered lesions on the scrotum and penis of patients that histologically resembled Paget’s disease of the breast.2 MPD and EMPD are cutaneous neoplasms with intraepithelial invasion of neoplastic cells that show glandular differentiation. These neoplasms tend to be found most commonly in areas with numerous apocrine or eccrine glands: the breasts, axilla, perianal and inguinal areas. Mammary Paget’s disease is traditionally associated with an underlying breast malignancy. Similarly, EMPD is associated with underlying malignancies. EMPD occurs most frequently in the anogenital or vulvar regions, but has also been reported in the axillae, penis, eyelids, umbilicus, groin, external auditory canal and cheek.3,4 Underlying malignancies occur in an average 25% of EMPD cases.5 Reported underlying cancers include bladder, urethral, endometrial, endocervical, vaginal, vulvar, prostatic, testicular, anal and rectal neoplasms.5-9 Clinically, EMPD most commonly presents with pruritus, sometimes associated with burning. The lesions often appear as scaly, eczematous patches or plaques with well-defined borders. Crusting and superficial erosions may also occur. Patients are often treated with steroid creams and antifungals before the correct diagnosis is made. Because these lesions are often initially misdiagnosed due to their similar clinical appearance to many benign processes, diagnosis is often delayed. As a result, these neoplasms are often diagnosed later in their course resulting in an average size at presentation of 3 cm to 5 cm.3 Extramammary Paget’s disease is a rare neoplasm, occurring most frequently in post-menopausal women, with a median age of 70 years.10 It is more frequently found in Caucasian populations and is rare in African-American patients.
Etiology and Pathogenesis
The histopathologic findings of mammary and extramammary Paget’s diseases are characterized by the presence of Paget’s cells. These are large cells with a larger, centrally located nucleus and abundant basophilic or amphophilic, finely granular cytoplasms. They might be single, in clusters or in nests. Paget's cells are most often concentrated down in adnexal structures, such as hair follicles or eccrine ducts. Immunohistochemistry is used in the identification of Paget’s cell. Cytokeratin 711 gross cystic disease fluid protein 15 (GCDFP-15), human milk fat globule membrane antigen (HMFG), EMA, and CEA are all found with high frequency in Paget’s cells. In addition, in more than 90% of cases of EMPD cases, tumor cells contain cytoplasmic mucin, and stain positively with periodic acid Schiff reagent. In contrast, only 40% of MPD tumor cells produce mucin.5 Ohnishi et al. noted that Paget’s specimens that did not stain cytokeratin7+/cytokeratin 20- had a higher likelihood of being associated with a regional underlying malignancy.12 The etiology of EMPD is unknown, but there are several theories as to its origin. Some believe that during embryogenesis, pluripotential germ cells within the epidermis go awry in the process of becoming apocrine structures, resulting in Paget’s cells. Also, it is uncertain as to where the Paget’s disease originates within the epithelium. Some theories suggest that adenocarcinoma begins in the epidermis and spreads to the epithelium of hair follicles and eccrine sweat ducts. It has also been suggested that EMPD starts in the epidermis and spreads to the dermis where it metastasizes. A third theory suggests that adenocarcinoma begins in the genitourinary or gastrointestinal tract and then spreads in the contiguous epidermis of the skin.13 Treatment The main treatment for non-invasive EMPD is surgical excision with wide margins. The recurrence rate for EMPD is very high, from 32% to 50% for male genital EMPD and 50% to 70% for perianal disease.14 Because of the high recurrence rate, 2 cm to 5 cm margins are recommended for EMPD excision. We recommend Mohs surgery for EMPD excision so that negative surgical margins can be confirmed before the defect is repaired. Preoperative use of 5-Fluorouracil (Efudex) or photodynamic therapy with topical 5-aminolevulinic acid (ALA) for 16 to18 hours followed by woods lamp examination have been used to assist in determining the subclinical extent of the tumor.11 After the wide excision, skin grafts or flaps are often utilized in reconstruction.15 A recent retrospective study showed a lower recurrence rate with the Mohs procedure versus local wide excision.11 In addition to surgical treatment, other treatment options have been reported to adjunctively or fully treat EMPD. Radiation therapy has been utilized in the past for patients who were not good candidates for excision, had primary limited cutaneous disease, or who needed adjuvant therapy.16 Systemic chemotherapeutic regimens that have been used for EMPD include carboplatin, bleomycin, calcium folate and 5-fluorouracil.14 Laser treatments have also been employed in managing the disease. Neodynium/yttrium aluminum garnet (Nd:YAG)17 and carbon dioxide laser ablation18 with and without concurrent photodynamic therapy have been reported with success. Imiquimod (Aldara), an amine that stimulates immune function, has had recent success with EMPD and appears to be a good option for patients who are poor surgical candidates.15