Clinical Investigation
Role of Radiotherapy as Curative Treatment of Extramammary Paget’s Disease

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Purpose

Extramammary Paget’s disease (EMPD) is a relatively rare malignancy that usually arises in the genital areas. Wide surgical excision remains the standard and most reliable curative treatment of EMPD. However, surgery is sometimes not possible, because many patients are elderly, and complete excision can be difficult owing to the tumor location. We, therefore, performed a review to determine the role of radiotherapy (RT) for EMPD.

Methods and Materials

A total of 22 patients with EMPD in their external genitalia (4 men and 18 women, age 52–94 years at RT) underwent RT with curative intent. Nine patients had regional lymph node metastases. A total dose of 45–70.2 Gy (median, 60) was delivered to the pelvis, including the tumors, in 25–39 fractions (median, 33).

Results

In all but 3 patients, the irradiated tumors were controlled during a follow-up period of 8–133 months (median, 42). Of the 22 patients, 13 developed recurrences, including local progression within the radiation field in 3 and lymph node and/or distant metastases outside the radiation field in 10, at 3–43 months after treatment. The 2- and 5-year local progression-free rates were 91% and 84%, respectively. Of the 22 patients, 7 patients had died at 33–73 months after RT. The cause of death was tumor progression in 4, infectious pneumonia in 2, and renal failure in 1 patient. The overall and cause-specific survival rates were 100% for both at 2 years and 53% and 73% at 5 years, respectively. No therapy-related Grade 3 or greater toxicity was observed.

Conclusions

RT is safe and effective for patients with EMPD. It appears to contribute to prolonged survival as a result of good tumor control.

Introduction

Extramammary Paget’s disease (EMPD) is a comparatively rare malignancy that often develops in the genital areas, including the vulva, scrotum, penis, and perineal and perianal regions, and less frequently in the axilla and umbilicus, in women aged 50–80 years. This neoplasm is considered to derive from the apocrine gland, but its etiology is still unclear. In 1874, Sir James Paget reported an intraepithelial neoplasm of the areola in the breast that was termed “Paget disease” (1). EMPD, which involved similar intraepithelial lesions in the skin of the scrotum and penis, was first described by Crocker (2) in 1888.

The disease sites generally present as relatively well-defined erythematous eczema or erosions, with or without leukokeratotic plaques, together with complaints of pruritus, irritation, or burning 3, 4, 5. However, EMPD will be asymptomatic in approximately 10% of patients. EMPD limited to the epidermis, so-called carcinoma in situ, is usually slow growing, with no change in the disease status for a period of ≥10 years in some cases. The diagnosis can accordingly be delayed, and the average interval between the onset of symptoms and diagnosis has been reported to be 2 years 4, 6. However, once the tumor invades into the dermis, it frequently makes rapid progress, resulting in lymph node and distant metastases. No well-established cures exist to treat patients with distant metastases of EMPD, and early detection and treatment while the disease is limited to the epidermis are of great importance. Additionally, EMPD frequently coexists with other internal malignancies; thus, a through examination to identify other malignancies should be performed before treatment 3, 4, 5, 6. Racial differences in the frequency of malignancies coexisting with EMPD have been reported, with the coexistence rate lower for Asian patients than for white patients (0–13% vs. 15–30%) (7).

Microscopically, Paget’s cells classically show abundant clear cytoplasm and large round-to-oval nuclei. They are distributed as single cells, strands, nests, or gland-like structures within the epidermis and epithelium of adnexal structures, with infiltration into the dermis at more advanced stages. However, the epidermal spread of other invasive cancers, such as genitourinary, colorectal, or anal canal carcinoma, or other intraepithelial neoplasms, such as squamous cell carcinoma in situ or intraepithelial melanoma, can occasionally mimic EMPD. Immunohistochemistry has been reported to be useful for differentiating between EMPD and these other malignancies and has been routinely used to definitively diagnose EMPD at our institution 8, 9, 10. Paget’s cells are generally positive for sweat gland markers such as cytokeratin 7 and gross cystic disease fluid protein 15 but are usually negative for markers of the epithelium and mucous membrane, such as cytokeratin 20 and cytokeratin 34βE12.

Wide surgical excision is currently the standard and most reliable curative treatment of EMPD 3, 4. However, surgical excision is sometimes not possible owing to the high incidence of elderly patients and the difficulties associated with aggressive surgery in the areas where the tumors are usually located. Although radiotherapy (RT) is applied to these medically inoperable patients and to patients who refuse surgery, few reports have been published of the results of RT. Therefore, we performed a retrospective review of patients with EMPD treated with RT with curative intent. We present the treatment outcomes and discuss the role of RT in EMPD.

Section snippets

Patients

Between October 1998 and January 2007, a total of 22 patients with EMPD underwent RT with curative intent at our institution. The exclusion criteria included distant metastases and poor general condition (Eastern Cooperative Oncology Group performance status ≥3) (11). Of these patients, 4 were men and 18 were women, and their age at RT was 52–94 years (median, 72). The primary tumor sites were the vulva in 10 patients, perineum in 7, and scrotum in 5. The maximal diameter of the visible tumors

Tumor control and failure patterns

All irradiated tumors had macroscopically disappeared by 2–9 months after RT, and the initial complete response rate was 100%. Photographs of the tumor site in 2 patients before and after RT are shown in Fig. 1, Fig. 2. However, 13 of the 22 patients had developed recurrence 3–43 months after RT. Of these 13 patients, 3 had developed local progression within the radiation field and 10 had developed lymph node or distant metastases outside the radiation field, during a follow-up period of 8–133

Discussion

Although the most standard and reliable curative treatment of EMPD is surgery, and wide excision is usually performed as the first choice treatment, the incidence of positive surgical margins and local recurrence is high, reaching 36–71% and 15–61%, respectively, after surgery 4, 14, 15, 16, 17, 18. Accordingly, Mohs micrographic surgery, in which frozen sections from all surgical margins are evaluated during surgery, is considered a useful strategy for EMPD. Several investigators have reported

Conclusions

Radiotherapy was effective and safe in our patients with EMPD and appeared to contribute toward prolonged survival as a result of good tumor control. The optimal radiation dose for EMPD remains unknown; however, a total dose of ≥60 Gy may be required to control gross tumors. EMPD with tumor invasion into the dermis frequently leads to lymph node metastasis, and prophylactic RT of the inguinal and pelvic lymph nodes is recommended for these patients. Microscopic diseases such as potential lymph

References (47)

  • J. Geisse et al.

    Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from two phase III. randomized, vehicle-controlled studies

    J Am Acad Dermatol

    (2004)
  • F. Raspagliesi et al.

    Photodynamic therapy using a methyl ester of 5-aminolevulinic acid in recurrent Paget’s disease of the vulva: A pilot study

    Gynecol Oncol

    (2006)
  • C. Louis-Sylvestre et al.

    Paget’s disease of the vulva: Results of different conservative treatments

    Eur J Obstet Gynecol Reprod Biol

    (2001)
  • J. Paget

    On disease of the mammary areola preceding cancer of the mammary gland

    St Bartholomew’s Hosp Rep

    (1874)
  • Crocker HR. Paget’s disease affecting the scrotum and penis. Trans Pathol Soc Lond...
  • J. Kanitakis

    Mammary and extramammary Paget’s disease

    J Eur Acad Dermal Venereol

    (2007)
  • V. Shepherd et al.

    Extramammary Paget’s disease

    BJOG

    (2005)
  • N. Hatta et al.

    Extramammary Paget’s disease: Treatment, prognostic factors and outcome in 76 patients

    Br J Dermatol

    (2008)
  • K.Y. Lee et al.

    Comparison of Mohs micrographic surgery and wide excision for extramammary Paget’s disease: Korean experience

    Dermatol Surg

    (2009)
  • B. Liegl et al.

    Mammary and extramammary Paget’s disease: An immunohistochemical study of 83 cases

    Histopathology

    (2007)
  • R.R. Raju et al.

    Pagetoid squamous cell carcinoma in situ (pagetoid Bowen’s disease) of the external genitalia

    Int J Gynecol Pathol

    (2003)
  • T. Ohnishi et al.

    The use of cytokeratin 7 and 20 in the diagnosis of primary and secondary extramammary Paget’s disease

    Br J Dermatol

    (2000)
  • M.M. Oken et al.

    Toxicity and response criteria of the Eastern Cooperative Oncology Group

    Am J Clin Oncol

    (1982)
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