Photodynamic therapy with M-ALA as non surgical treatment option in patients with primary extramammary Paget's disease

https://doi.org/10.1016/j.ygyno.2013.04.008Get rights and content

Highlights

  • Treatment of recurrent primary extramammary Paget's disease with photodynamic therapy is safe and feasible.

  • After three courses of photodynamic therapy lesion size and symptoms are significantly reduced in patients with extramammary Paget's disease.

Abstract

Introduction

Extramammary Paget disease (EMPD) is a rare neoplasm of the skin that presents with erythematous or leukoplacic plaques causing pruritus and pain. Standard treatment is surgical but local failures and recurrences are frequent, leading to multiple mutilating surgeries. Aim of the study is to evaluate the effectiveness of photodynamic therapy (PDT) to obtain a clinical response and symptom control with a non surgical approach in these patients.

Materials and methods

After disease extension evaluation and symptoms assessment women with EMPD were prospectively treated with aminolevulinic-acid methyl-esther (M-ALA) PDT. Clinical and symptoms response were evaluated after 3 cycles and after any further PDT.

Results

Thirty-two patients with vulvar EMPD underwent M-ALA PDT. In sixteen (50%) patients the lesion extended to the perineal and/or perianal area. After three courses of treatment, three patients (9.4%) had a complete resolution of the symptoms; 25 patients (78.1%) a partial resolution and a stable disease was recorded in four patients (12.5%). None of the patients had progression of disease. Both size of the lesion and EMPD associated symptoms decreased significantly after three courses of treatment. Eighteen patients (56.2%) recurred and 16 (88.9%) were treated with further PDT. Among the 26 patients who underwent a further PDT, 16 patients (61.5%) achieved at least a partial response.

Conclusion

M-ALA PDT even if not curative is a reliable strategy to control EMPD and its associated symptoms even in an outpatient setting. M-ALA PDT is able to control large and multiple lesions regardless of the area involved, preserving cosmetic and/or functional anatomy.

Introduction

Extramammary Paget disease (EMPD) is a rare neoplasm of the skin which was first described by Crocker in 1889, 15 years after the description of its mammary localization [1]. Its exact incidence is unknown but it is estimated to account for 1 to 6% of all cases of Paget's disease and predominantly affects women 60 years or older [2].

EMPD is mainly localized to apocrine-gland-bearing regions such as vulvar and perineal skin, whereas the mucosa of the labia minora, urethra, bladder and endocervix is less frequently involved. The lesions typically present as erythematous or leukoplacic plaques. Symptoms such as pruritus, pain and a burning sensation are common and explain why these lesions are often misdiagnosed as dermatitis or as a fungal infection thus delaying diagnosis.

EMPD can be classified into primary or secondary based on the site of origin of the neoplasm:

  • 1.

    Primary or cutaneous EMPD is defined as an intraepithelial adenocarcinoma originating in the skin (epidermis or underlying apocrine sweat glands). Its precursor cell seems to be an undifferentiated multipotent cell of the epidermis and/or cutaneous adnexa. Epidermal Toker cells are also considered to be precursors of Paget's cells. Primary EMPD rarely progresses into an invasive tumor and metastases are therefore uncommon.

  • 2.

    Secondary EMPD is the expression of a metastatic diffusion to the skin by an underlying adenocarcinoma. Ano-rectal adenocarcinoma and urothelial carcinoma represent the most frequent causes of secondary Paget's disease. Given the high incidence of underlying adenocarcinomas a thorough work up of the patients including a physical examination, mammogram, cystoscopy, colonoscopy and abdomino-pelvic sonogram or computed tomography (CT) aimed to the identification of the primary malignancy is recommended [3].

Standard of care for EMPD is surgical excision. However, unlike the more common squamous cell carcinoma of the vulva, EMPD is often multifocal and has an indistinct demarcation without correlation between gross and microscopic border of the lesion, leading often to positive resection margins and high rates of local failures. Since surgical excision is the mainstay of treatment for local recurrences as well, a significant number of patients with EMPD will undergo multiple resections that may ultimately lead to anatomic and function alterations.

In order to decrease the morbidity associated to multiple surgical excisions alternative conservative treatments have been proposed [4], [5], [6], [7]. Unfortunately, to date, only few and inconclusive data on the real efficacy of these treatments are available and they cannot be considered as a solid alternative to surgical excision yet.

Since the first successful experiences in various cutaneous intraepithelial tumors, photodynamic therapy (PDT) has been employed in EMPD. PDT is based on a photochemical reaction induced by a combination of an oncophilic photosensitizing agent and light [8], [9]. In theory, a topical photosensitizer selectively localizes in the neoplasia and, when activated by light, destroys the target tissue, sparing the healthy tissue. Aminolevulinic acid (ALA) or its methyl esther (M-ALA) are the most commonly employed photosensitizers. Recent studies have shown good results in terms of response rates and symptom control in EMPD [10], [11], [12].

Following the encouraging results of our pilot study demonstrating the feasibility and efficacy of PDT in terms of clinical response and symptoms relief in patients with recurrent Paget's disease of the vulva, a phase II prospective clinical trial on the management of EMPD with M-ALA PDT was started at our Institution [13]. Great focus was placed on assessing the risk of local progression and metastatic spread, in order to evaluate the possibility to control Paget's disease only by non surgical methods.

Section snippets

Materials and methods

After Institutional Review Board approval from the National Cancer Institute of Milan was obtained, female patients with histologically confirmed primary EMPD were prospectively enrolled from June 2007 to December 2011 for M-ALA PDT. Patients with recurrent EMPD and patients at initial diagnosis refusing surgical excision were included. All patients provided written informed consent. Pap smear, clinical examination, abdomino-pelvic sonogram, hemoccult and bilateral mammography were requested

Results

Thirty-three patients presented during the study period to our Institution with EMPD. At work up a subcutaneous adenocarcinoma was detected in one patient who was excluded from the study and underwent appropriate surgical treatment. The remaining 32 patients underwent M-ALA PDT. All patients had histologically confirmed EMPD and in four cases (12.5%) a stromal invasion not exceeding 1 mm in depth, consistent with minimal invasion according to the World Health Organization definition, was

Discussion

Primary intraepithelial Paget's disease can be considered as a chronic disease with an indolent clinical course. It is not unusual for EMPD to persist without progression for long periods of time. Prognosis is also very favorable with an 85% 5-year survival. Because EMPD is an extremely rare clinical entity, our understanding of this disease is still limited and treatment often leads only to suboptimal results.

Surgical excision is the current standard of care for patients with primary EMPD at

Conflict of interest statement

No funds have been received.

None of the authors has a conflict of interest.

All authors have no financial disclosures.

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