Paget's disease of the vulva: A review of 89 cases

Abstract

The purpose of this study was to retrospectively review the clinical characteristics and outcomes of a series of women with Paget's disease of the vulva. A retrospective review was performed of 89 women with Paget's disease of the vulva evaluated at a single institution between 1966 and 2010. Medical records were reviewed for demographic information, clinical data, pathologic findings, treatment modalities and outcomes. We found that the primary treatment was surgery for 74 (83.1%) patients, with positive margins noted in 70.1% of cases. Five patients (5.6%) underwent topical treatment with imiquimod and/or 5-fluorouracil, one patient (1.1%) underwent laser ablation and treatment was unknown in 9 patients (10.1%). The majority of patients had multiple recurrences, with 18% having four or more recurrences. There were no significant differences in recurrence rates between patients who underwent surgery and those who did not. Furthermore, there was no association between positive margins following primary surgery and recurrence. Forty-one patients (46.1%) were diagnosed with 53 synchronous or metachronous cancers. Seven patients (7.9%) were found to have invasive vulvar cancer with 1 mm or more depth of invasion, but none of the patients died of Paget's disease or associated vulvar/vaginal cancer. Our findings suggest that the majority of patients with Paget's disease of the vulva develop multiple recurrences regardless of treatment modality or margin status. Alternatives to surgery are needed to better care for women with this disease.

Highlights

• •Many recurrences were noted regardless of margin status following surgery for Paget's disease.
• •46% of the patients with Paget's disease had synchronous or metachronous cancers.
• •None of the patients in our study died of Paget's disease or associated vulvar cancer.
• •Alternatives to surgery are needed to improve outcomes in these patients.

1. Introduction

Paget's disease of the vulva is a rare vulvar neoplasm most commonly seen in postmenopausal women. Mammary Paget's disease involving the nipple and areola was first described by Sir James Paget in 1874 (Paget, 1874). Subsequently in 1889, Dr. Crocker reported the first case of extramammary Paget's disease affecting the scrotum and penis (Crocker, 1889). Paget's disease of the vulva was first reported in 1901 by Dr. Dubreuilth (Dubreuilh, 1901).

Paget's disease of the vulva usually presents as a pink eczematous lesion with white islands of hyperkeratosis accompanied by pruritus. Pathologically it resembles mammary Paget's of the nipple and areola. It is a disease more often diagnosed in Caucasian, postmenopausal women (Kay and Southwood, 1964, Tebes et al., 2002, Black et al., 2007). Patients with Paget's disease of the vulva are at risk for a second synchronous or metachronous neoplasm: colorectal adenocarcinoma, cervical adenocarcinoma, carcinoma of the transitional epithelium from the renal pelvis to urethra, breast and vulvar carcinoma (Preti et al., 2000, Onaiwu et al., 2014). Routine screening with colonoscopy, Pap test, mamogram and cystoscopy is therefore recommended (Tebes et al., 2002, Feuer et al., 1990).

Paget's disease of the vulva is often limited to the epidermis and mucosa without invasion. The optimal management of Paget's disease of the vulva remains unclear. Surgical excision is usually the primary therapy (Edey et al., 2013). Furthermore, the lesions often extend past clinically apparent borders resulting in positive margins, and surgical excision is limited by the anatomy of the vulva. In addition, the disease is often multifocal and many patients require multiple excisions resulting in significant morbidity. Alternative treatment strategies are therefore needed. The objective of our study was to determine prognostic factors, risk factors for recurrence, associated malignancies, and outcomes of some treatment methods for Paget's disease of the vulva.

2. Methods

We performed a retrospective chart review of 89 patients with Paget's disease of the vulva evaluated at the University of Texas MD Anderson Cancer Center between 1966 and 2010. Institutional Review Board approval was obtained with a waiver of informed consent. Medical records were reviewed for demographic information, clinical data, pathologic findings, treatment modalities, and outcomes. Eligible patients were identified using databases from the Departments of Gynecologic Oncology and Pathology. Pathologic diagnosis of Paget's disease of the vulva for all patients was confirmed by a Gynecologic Pathologist at the University of Texas MD Anderson Cancer Center. Invasive Paget's disease was defined as disease extending beyond the basement membrane. Invasive cancer was defined as ≥ 1 mm of invasion.

A positive margin was defined as Paget's cells within 1 mm of the surgical margin. Residual disease was defined as Paget's cells found in the pathology specimen of the subsequent procedure is performed within three months of the prior procedure. If the subsequent procedure was performed after three months, this was considered recurrent disease. The follow-up period was defined as the time between initial Paget's disease diagnosis and the date of last contact.

Descriptive statistics were used to summarize the patient demographic and clinical characteristics. Fisher's exact test was used to compare patients with recurrence to those without recurrence with respect to types of primary treatment received and margin status among those patients with primary surgery. Study data were collected and managed using REDCap electronic data capture tools hosted at MD Anderson (Harris et al., 2009). REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies.

3. Results

Eighty-nine patients were identified that met inclusion criteria for the study. The median age at diagnosis was 67 years (range: 32–89 years). The majority of patients were Caucasian (n = 83, 93.3%). The median duration of symptoms prior to diagnosis was 10 months (range: 1–204 months). The main presenting symptom was pruritus (n = 43, 48.3%).

Primary treatment consisted of surgery for 74 (83.1%) patients including wide local excision (n = 55, 61.8%), radical vulvectomy (n = 13, 14.6%), skinning vulvectomy (n = 4, 4.5%), and Mohs surgery (n = 2, 2.3%). Margin status was available for 54 (73.0%) of the 74 patients who had surgery as primary treatment. Of these 54 patients, 47 (87.0%) were found to have positive margins. Five (5.6%) patients underwent topical treatment as primary therapy with imiquimod (n = 4, 4.5%) or 5-fluorouracil (n = 1, 1.1%). One (1.1%) patient underwent laser ablation (Table 1).

Table 1.

Primary treatment (n = 89).

Primary treatment	N (%)
Surgery:	74 (83.1%)
Wide local excision	55 (61.8%)
Radical vulvectomy	13 (14.6%)
Skinning vulvectomy	4 (4.5%)
Mohs surgery	2 (2.3%)
Topical therapy:	5 (5.6%)
Imiquimod	4 (4.5%)
5-Fluorouracil	1 (1.1%)
Laser ablation	1 (1.1%)
Unknown	9 (10.1%)

Fifty-two (58.4%) patients developed recurrent disease following primary treatment (Table 2). The majority of patients had multiple recurrences, with 18.0% of patients having four or more recurrences, including one patient who was treated for 10 recurrences (Onaiwu et al., 2014). The most common treatment for recurrent disease was surgery with 38 of the 52 patients (73.1%) undergoing one or more procedures, 21 (40.4%) patients underwent two or more surgical procedures, and 10 (19.2%) underwent three or more surgical procedures. Topical therapies with imiquimod and/or 5-fluorouracil were also used for recurrent disease in 23 (44.2%) patients.

Table 2.

Recurrent disease (n = 89).

Number of recurrences	N (%)
0	37 (41.6%)
1	20 (22.5%)
2	11 (12.4%)
3	5 (5.6%)
4	7 (7.9%)
5	5 (5.6%)
6	0 (0.0%)
7	1 (1.1%)
8	2 (2.2%)
9	0 (0.0%)
10	1 (1.1%)

Recurrence rates were compared by primary treatment modality (Table 3). There were no significant differences in recurrence rates in patients who underwent surgery and those who did not. There also were no significant differences by type of surgery. There also was no association between positive margin status at time of primary surgery and recurrence, with 26/47 (55.3%) with positive margins developing recurrent disease compared with 4/7 patients (57.1%) with negative margins developing recurrent disease (p = 0.9999). Seven (7.9%) patients were diagnosed with invasive vulvar/vaginal cancer with 1.0 mm or more depth of invasion (Table 4).

Table 3.

Recurrence rates by treatment modality.

	No recurrence (N = 37)	Recurrence (N = 52)	p-Value
Primary surgery (n = 74):	28 (37.8%)	46 (62.2%)	NS
Wide local excision (n = 55)	19 (34.5%)	36 (65.5%)
Radical vulvectomy (n = 13)	7 (53.8%)	6 (46.2%)
Skinning vulvectomy (n = 4)	2 (50.0%)	2 (50.0%)
Mohs surgery (n = 2)	0 (0.0%)	2 (100.0%)
Margin status (n = 74):			NS
Positive margins (n = 47)	21 (44.7%)	26 (55.3%)
Negative margins (n = 7)	3 (42.9%)	4 (57.1%)
Unknown margin status (n = 20)	4 (20.0%)	16 (80.0%)
Topical therapy (n = 5):	1 (20.0%)	4 (80.0%)	NS
Imiquimod (n = 4)	1 (25.0%)	3 (75.0%)
5-Fluorouracil (n = 1)	0 (0.0%)	1 (100.0%)
Laser ablation (n = 1)	0 (0.0%)	1 (100.0%)	NS
Unknown (n = 9)	8 (88.9%)	1 (11.1%)	NS

Table 4.

Patients with invasive vulvar cancer.

Patient number	Diagnosis	Stage	Treatment	Outcome
1	Invasive Paget's disease (2.5 mm of invasion)	I	Wide local excision	Alive with Paget's disease
2	Adenocarcinoma (multifocal) in a background of Paget's disease (2.5 mm of invasion)	III	Wide local excision; radiation therapy	Deceased due to other causes
3	Poorly differentiated carcinoma of the vagina in a background of Paget's disease (unknown depth of invasion)	II	Wide local excision; radiation therapy	Deceased due to other causes
4	Invasive adenocarcinoma in a background of Paget's disease with lymph node involvement (unknown depth of invasion)	III	Unknown	Deceased due to other causes
5	Invasive Paget's disease (1.3 mm of invasion)	I	Wide local excision	Deceased due to other causes
6	Invasive Paget's disease (> 1.0 mm of invasion)	III	Radical vulvectomy	Deceased due to other causes
7	Poorly differentiated carcinoma in a background of Paget's disease (4.5 mm of invasion)	No	Radical vulvectomy; radiation therapy	Deceased due to other causes

Forty-one of the 89 patients (46.1%) with Paget's disease were diagnosed with 53 synchronous (92.7%) or metachronous (7.3%) cancers. Of those with metachronous cancers, the time between Paget's diagnosis and cancer diagnosis ranged from 2 weeks to 19 years. The most common types included breast (n = 13, 14.6%), bladder (n = 6, 6.7%), colorectal (n = 5, 5.6%), and endometrial (n = 4, 4.5%). Follow-up data were available for 81 patients, with a median follow-up of 6.1 years (range 0–34.1). At date of last contact, 19 (23.5%) patients were alive without evidence of disease, 25 (30.9%) were alive with active Paget's disease, and 45 (55.6%) have died of other causes. None of the patients in our study died of Paget's disease or associated vulvar cancer.

4. Discussion

The principal finding from our study is that the majority of patients with Paget's disease of the vulva develop multiple recurrences regardless of treatment modality or margin status following surgery. In addition, we noted that 46% of the patients with Paget's disease of the vulva had synchronous or metachronous cancers. Seven (7.9%) patients were found to have invasive vulvar/vaginal cancer, but none of the patients died of Paget's disease or associated vulvar/vaginal cancer.

In 2013, Edey et al. (Edey et al., 2013) published a Cochrane review evaluating the different treatment modalities for Paget's disease of the vulva. They found that no study satisfied their initial inclusion criteria (randomized control trials and well-designed non-randomized studies that compared interventions in women with biopsy confirmed vulvar Paget's disease) due to poor quality and high risk of bias. Instead they did a comprehensive narrative of 20 retrospective studies that included a total of 581 women. They found that the most common treatment modality was surgery with a majority of women undergoing wide local excision (35%) and radical vulvectomy (27%). Most studies determined that margin status had no impact on chance of recurrence; however, margin status was known in only 57% of the women. Furthermore, it could not be determined whether or not more radical versus conservative surgery impacted the recurrence rate. In 2011, Mendivil et al. (Mendivil et al., 2012) concluded that the presence of microscopic positive margins and lesion size had no correlation with disease recurrence. In 2002, Tebes et al. (Tebes et al., 2002) found that margin status did not impact recurrence rate. These findings are similar to our study where we found no association between margin status and recurrence rates. In addition, the Cochrane review (2013) provided survival data for 306 women, and at least 13% were found to have cancer at another site with 3.2% being metachronous. They concluded that there was no reliable evidence to inform decisions about different interventions for women with Paget's disease of the vulva (Edey et al., 2013).

In 2011, Jones et al. (Jones et al., 2011) performed a retrospective study of 50 cases from Queensland, Australia reviewing the clinical features, diagnosis, management, and outcomes of women treated for Paget's disease of the vulva. The study determined that of the 12 patients who died, two died of Paget's disease both of which had widespread disease at the time of death. One of the Paget's disease related deaths was a 31 year-old woman who underwent four biopsies and six excisions prior to her death at age 42. Treatment modalities evaluated in the study were primary surgery, including wide local excision, radical vulvectomy, partial vulvectomy with and without groin dissection, and surgery followed by radiation. Other primary treatment modalities included chemotherapy for those cases with confirmed aortic and groin node adenocarcinoma or carcinoma. Margin status was unknown in 16% of cases. In total, 54% of the patients in this study with a confirmed positive margin were still alive after one to 17 years, and 7 of them had recurrence. Twenty percent of patients had another malignancy, a majority with breast cancer. The study concluded that long-term follow up is necessary for optimal management of Paget's disease of the vulva. Furthermore, it deems margin status post excision as unreliable (Jones et al., 2011).

In 2012, Mendivil et al. (Mendivil et al., 2012) conducted a review assessing the clinicopathologic characteristics of patients with Paget's disease of the vulva treated at their institution. The study analyzed 16 patients diagnosed, treated, and followed at a single institution over 25 years. A majority of the patients analyzed (81.3%) had primary intraepithelial Paget's disease, and 18.8% had invasive disease. A history of a second malignancy was noted in 18.8% of patients, a majority being breast cancer. Treatment modalities included simple vulvectomy (62.5%), radical vulvectomy (18.8%), expectant management following biopsy (12.5%), and hysterectomy (6.3%). The study concluded that the presence of microscopic positive margins and lesion size had no correlation with disease recurrence. However, there was a prognostic relationship between the presence of invasive disease and disease recurrence (Mendivil et al., 2012). Parker et al. performed a retrospective study of 76 patients to evaluate risk factors and prognostic factors for recurrence in Paget's disease of the vulva. The authors concluded that patients treated with wide local excision had a higher risk of recurrence, but overall they tended to survive longer than patients treated more radically. In our study there were no significant differences in recurrence rates by type of surgery (Parker et al., 2000).

In 2002, Tebes et al. (Tebes et al., 2002) evaluated 23 women treated for Paget's disease of the vulva at the University of South Florida over the course of 12 years. Treatment modalities included wide local excision or radical vulvectomy with groin node dissection if invasive disease was found. Forty-six percent of women with intraoperative negative margins were found to have positive margins on final pathological reports. Margin status did not impact recurrence rate and this study population had a recurrence rate of 35% with mean time to relapse of 30 months. Twenty-two percent of the patients evaluated had other malignancies, a majority being breast cancer. Invasive vulvar disease was found in 26% of patients. The study suggests that despite significant delay between onset of symptoms and diagnosis, there was no correlation with size or extent of disease. Their study recommended long-term monitoring with repeat excision of symptomatic lesions (Tebes et al., 2002).

Our study is limited by retrospective data collection, a long study period and data from a single institution with possible referral bias. In addition, no centralized pathology review was performed specifically for this study, however all cases were reviewed by a Gynecologic pathologist. Despite these limitations, this study included a large number of patients with Paget's disease of the vulva to help gain a better understanding of this uncommon and often chronic disease. Given the large number of recurrences following surgery regardless of margin status, alternatives to surgery are needed to improve outcomes in these patients. A recent study by Cowan et al. (Cowan et al., 2016) evaluated the use of imiquimod in eight patients with recurrent Paget's disease of the vulva. They noted a complete histologic and clinical response in six patients (75%) and a complete clinical but not pathologic response in one additional patient. None of the patients progressed to invasive cancer while on imiquimod treatment. In our study, four patients were treated with imiquimod with one patient having a long term, sustained response. These findings support further investigation into non-surgical options such as imiquimod for the treatment of Paget's disease of the vulva.

Conflict of interest statement

The authors do not have any conflicts of interest to disclose.