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Extramammary Paget disease

  • Author(s): Hartman, Rachael
  • Chu, Julie
  • Patel, Rishi
  • Meehan, Shane
  • Stein, Jennifer A
  • et al.
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Extramammary Paget disease
Rachael Hartman MD, Julie Chu MD, Rishi Patel MD, Shane Meehan MD, Jennifer A Stein MD PhD
Dermatology Online Journal 17 (10): 4

Department of Dermatology, New York University, New York, New York

Abstract

We report the case of a 60-year-old man with penile-scrotal extramammary Paget disease (EMPD). The patient initially underwent Mohs micrographic surgery, but the margins remained positive after several sections; multiple scouting punch biopsies used to define the extent of the tumor were also positive. Because of concerns about functional impairment and cosmesis associated with wide local excision, the patient instead chose treatment with topical 5 percent imiquimod cream as a cytoreductive and margin-defining treatment. Owing to the association between EMPD and underlying malignant conditions, a thorough metastatic evaluation is necessary, particularly to rule out genitourinary cancer in the setting of penile-scrotal EMPD. Management of EMPD is complicated by the multifocal, non-contiguous nature of the disease and the presence of clinically occult extensions. As a result, recurrence rates after surgery are high. Several non-surgical modalities have been used to treat EMPD, which include radiotherapy, topical imiquimod, topical 5-fluorouracil, topical bleomycin, photodynamic therapy, CO2 laser ablation, and topical retinoids. Systemic chemotherapy also has been used to treat advanced EMPD. However, because EMPD is so uncommon, clinical trials comparing the various methods of treatment are lacking. Regardless of the mode of treatment, long-term follow up is essential, given the high rate of recurrence.



History

A 60-year-old man presented to the Charles C. Harris Skin and Cancer Pavilion in July, 2010, for management of a genital eruption. The patient first noticed painful, erythematous papules, hypopigmented patches, and superficial ulcers lateral to the right side of the base of the penis in April, 2009. He reported intermittent subjective fevers and chills, but denied weight loss, anorexia, change in bowel function, hematuria, dysuria, hesitancy, and urinary frequency. A diagnosis of eczema was made by an outside dermatologist. After the eruption failed to respond to several courses of treatment with topical glucocorticoids and topical antifungals, a biopsy was obtained in April, 2010. The initial biopsy specimen showed squamous cell carcinoma, but a subsequent biopsy specimen in May, 2010, showed a different malignant condition. The patient underwent Mohs micrographic surgery in May, 2010, with a 4 x 6 cm excision lateral to the right side of the base of the penis, but the margins were still positive after 12 sections. Twelve punch biopsies were taken at approximately 1 cm margins from around the entire base of the penis, six per side. Eight of the twelve biopsies were positive for a malignant condition, five of which were lateral and superior to the excision site and three of which were superolateral to the left side of the base of the penis. The patient was then referred to Medical and Surgical Oncology at Bellevue Hospital Center where 15 additional punch biopsies were performed to map the extent of the tumor, eight of which were positive from both sides of the base of the penis, the scrotum, and the right suprapubic area. Wide local excision with radiation was recommended, but the patient desired a second opinion about alternative treatment options because of concerns about functional impairment and cosmesis.

The patient was born in Shanghai and moved to the United States at age 40. He had no other pertinent medical history, took no systemic medications, and had no known allergies to medications. The patient reported that his mother died of Paget disease of the breast at age 67. At the time of presentation, he was on disability from a job in packaging.

The patient had been applying topical imiquimod 5 percent cream three times a week since July, 2010, with marked erythema, edema, and erosions on the scrotum and base of the penis. He had been applying mupirocin 2 percent cream daily to the erosions.


Physical examination


Figure 1Figure 2

Multiple, well-demarcated, erythematous, and hypopigmented plaques were present at the base of the penis, on the scrotum, and on the suprapubic area. The right side of the penis and scrotum was more involved than was the left side. There were no palpable masses on the scrotum or penis and no palpable inguinal lymph nodes.


Laboratory data

The hematocrit was 41.3 percent, lymphocytes 53.3 percent, and neutrophils 40.5 percent. A basic metabolic panel was normal except for an elevated glucose of 108 mg/dL. An anticoagulation panel was normal. Urinalysis showed trace blood. Urine culture and cytology were negative. Flexible cystoscopy showed vascularity that was suggestive of cystitis or inflammation but no discrete lesions. Chest radiograph, computed tomography urogram, and computed tomography scan of the abdomen and pelvis were normal.


Histopathology


Figure 3

Within the epidermis, there was a proliferation of cells with abundant pale eosinophilic cytoplasm that were arranged as nests and single units. Some nests compressed and flattened the cells of the basal layer of the epidermis.


Discussion

Extramammary Paget disease is an uncommon adenocarcinoma of apocrine gland-bearing skin. It usually occurs in individuals between the ages of 50 and 80 years and is more common in Caucasians and women [1, 2]. However, in Asian populations, men are more likely to be affected [3]. Considering all patients, the most frequently involved site is the vulva, followed by the perianal area, perineum, scrotum, penis, and axillae [4, 5]. Rarely, the thighs, buttocks, eyelid, and external ear canal may be affected [5, 6]. When EMPD occurs in non-apocrine bearing skin, it is called ectopic EMPD [2, 5].

Clinically, EMPD is characterized by a well-defined, erythematous or white patch or plaque that is often pruritic [2]. Delays in diagnosis are common owing to the non-specific clinical findings that can be difficult to distinguish from psoriasis, dermatophytosis, contact dermatitis, lichen sclerosis, squamous-cell carcinoma in situ, melanoma, and mycosis fungoides [5, 6].

Histopathologic examination of EMPD shows intraepidermal Paget cells, which are large, round cells with abundant pale-staining cytoplasm and a large nucleus. Immunohistochemical staining is important to confirm the diagnosis of EMPD. Cytokeratin 7 is the immunostain of choice for evaluating the margins in this tumor [7]. Immunostains also are necessary to distinguish EMPD (cytokeratin 7 positive, periodic acid-Schiff (PAS) positive, carcinoembryonic antigen (CEA) positive, S100 negative) from pagetoid melanoma (S100 positive, PAS negative, CEA negative, cytokeratin negative) and intraepithelial neoplasia (S100 negative, PAS negative) [5].

Although EMPD usually remains confined to the epidermis, it may invade the dermis and rarely metastasize via the lymphatic system. Prognosis depends on the depth of invasion. The prognosis for primary EMPD in situ is excellent, whereas invasive primary EMPD has a poor prognosis, particularly if there is lymphovascular invasion [5]. Thus, there may be a role for sentinel lymph node biopsy for staging of invasive EMPD [8].

All patients with EMPD should have a thorough metastatic evaluation because between 12 percent and 33 percent of cases are associated with an underlying malignant condition. Certain locations, such as perianal EMPD, have a higher risk of concomitant malignant condition than do others [1, 5, 9]. There is a much lower incidence of associated malignant conditions in Chinese men with genital EMPD than there is in Caucasians [3]. The location of the underlying malignant condition tends to correlate with the location of the EMPD. Penile-scrotal EMPD is associated with genitourinary cancers, whereas perianal EMPD is associated with gastrointestinal malignant conditions [10, 11].

Management of EMPD is challenging because of the multifocal, non-contiguous nature of the disease and the presence of clinically occult extensions [2, 5]. The standard treatment for EMPD is wide local excision or Mohs micrographic surgery (MMS), but recurrence rates are high. Recurrence rates after standard surgical excision range from 33 to 60 percent versus 16 to 28 percent after MMS [5, 12, 13]. The median time to recurrence is approximately 2.5 years and underscores the need for long-term follow up [9]. Not surprisingly, there is a higher rate of local recurrence among patients with invasive disease than there is in those with in situ disease [2, 5].

Several methods have been proposed to help delineate the margins of EMPD prior to surgery and include application of topical 5-fluorouracil or imiquimod to seemingly uninvolved edges, photodynamic diagnosis, fluorescein visualization, and multiple scouting biopsies [2, 13-16].

In response to the high recurrence rates after surgical management and the need for improved cosmetic and functional outcomes, several nonsurgical treatment modalities have been used to treat EMPD. Radiotherapy has been used successfully in patients with non-invasive EMPD and may be indicated for recurrence following surgery, for patients who are not surgical candidates, or as an adjuvant to surgery in patients with a high risk of local recurrences after surgery alone [2, 5, 17]. Topical imiquimod also has been used to successfully treat non-invasive EMPD although there is no consensus about the frequency or duration of treatment. Various treatment regimens that include daily application of imiquimod and application three times a week over a period of six to 12 weeks have been reported [9, 13, 18, 19]. Other treatment modalities include photodynamic therapy, CO2 laser ablation, topical retinoids, topical 5-fluorouracil, and topical bleomycin [2, 20]. Systemic chemotherapy also has been used to treat EMPD when surgery and radiation are contraindicated [2]. There was one report of successful treatment of advanced EMPD with a combination of low-dose 5-fluorouracil and cisplatin [21]. However, a standardized effective regimen has not been established.

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