Interventions for the treatment of Paget's disease of the vulva
Abstract
Background
Extra‐mammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non‐invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell‐specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery.
Objectives
To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva.
Search methods
We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to September 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles and contacted experts in the field.
Selection criteria
We searched for randomised controlled trials (RCTs) and well‐designed non‐randomised studies that compared different interventions in women with Paget's disease of the vulva,
Data collection and analysis
Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, no data were analysed.
Main results
The search strategy identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease.
Authors' conclusions
We found no reliable evidence to inform decisions about different interventions for women with Paget's disease of the vulva. Ideally, a multicentre RCT of reasonable size is needed. In particular, evidence regarding the increasing use of imiquimod would be helpful to women and clinicians alike. Well‐designed non‐randomised studies, that use multivariate analysis to adjust for baseline imbalances, as well as other key methodological strengths, are also lacking.
PICOs
Plain language summary
No evidence was available for the comparison of different interventions for women with Paget's disease of the vulva
Background
Extramammary Paget’s disease of the vulva is a rare type of superficial skin cancer. It is most common in postmenopausal white women. It is an intraepithelial (layer of cells that forms the surface or lining of an organ) condition that can present as white and red scaly areas on the vulva that may be itchy and painful. The diagnosis is made by examination and tissue sampling. Abnormal cells often extend outside the clinically abnormal area, so some studies suggest frozen section at time of surgery, where a pathologist can give a rapid report of small biopsies to say whether the skin is involved with Paget's or not. Other treatments include: topical medication, such as imiquimod (patient‐applied cream); radiotherapy; chemotherapy; photodynamic therapy (form of phototherapy using light‐sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted cancerous and other diseased cells); and laser therapy; or a combination of these approaches. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment. Avoiding the long‐term complications of radical surgery, such as pain and scarring, a feeling of mutilation and loss of femininity, is very important to women. Surgery is still the most common treatment, but it is challenging to remove the disease completely, and recurrence is common, leading to repeated operations, and mutilation of the vulva. The aim of this review was to evaluate the benefits and harms of different treatments for Paget's disease of the vulva.
Study characteristics
We searched for randomised controlled trials (trials where treatment is allocate to women in a random manner) and well‐designed non‐randomised studies that compared different treatments in women aged 18 years or older with biopsy‐confirmed Paget's disease of the vulva.
Key results and quality of evidence
We searched scientific databases and contacted experts and identified and checked the titles and abstracts of 635 possibly relevant articles and retrieved 31 of these references in full text. However, we found no studies that met our inclusion criteria. We identified a number of non‐randomised studies and drafted a detailed narrative of their results, but these studies were of poor quality and were at high risk of bias. Therefore, there is currently no evidence to determine whether any form of treatment is better or worse in terms of prolonging survival, delaying progression or recurrence, improving quality of life or minimising toxicity. The review highlights the need for good‐quality studies comparing different interventions for the management of Paget's disease of the vulva. Women and clinicians would value more evidence for guiding surgical and non‐surgical management of this disease. In particular, non‐invasive medical management would spare women from the adverse effects and consequences of surgery.
Authors' conclusions
Background
Description of the condition
Extra‐mammary Paget's disease is a rare form of intraepithelial skin cancer (adenocarcinoma). The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. It is characterised by infiltration of the squamous mucosa or adenexa by vacuolated Paget cells. It is an intraepithelial adenocarcinoma that presents as slowly expanding, asymmetrical white and red scaly plaques on the vulva, which may be itchy and painful. The diagnosis is made by finding the characteristic changes on skin biopsy. Immunohistochemistry is required to exclude the differential diagnoses of melanoma and vulval intraepithelial neoplasia. Paget's disease may be primary, arising as an intraepithelial adenocarcinoma, or secondary due to Pagetoid spread of an adjacent or contiguous in situ or invasive tumour. There have been reports of an association with distant tumours, particularly breast cancer, although the strength of this association is unknown. Any screening for distant tumours may involve lengthy and invasive investigations, and also delay the appropriate treatment of the Paget's disease itself (Heymann 1993; Kanitakis 2007). Immunohistochemical stains can guide further investigations. Tissue staining negative for cytokeratin 20 favours a cutaneous origin for Paget's (primary or secondary due to an underlying adnexal adenocarcinoma) and positive staining favours an endodermal origin, where a visceral malignancy should be more keenly sought. The presence of Paget’s disease around the perianal area or around the urethra should prompt a search for urothelial or rectal tumours. One clinicopathological study in 1977 reported 13 cases of Paget's disease of the vulva (Lee 1977): four (31%) of the women had underlying invasive carcinoma of the adnexal structures and three (23%) had adnexal carcinoma in situ. In four women (31%), a second malignancy was found (Lee 1977). A more recent case series reviewed 10 women with vulval Paget's disease (Fanning 1999). About 34% of patients recurred, at a median time interval of three years, with 12% having invasive Paget's disease of the vulva and 4% had a vulval adenocarcinoma. The association between Paget's disease and other malignancies is variable across the literature, with one literature review showing the association to be between 0% and 50%, and with no significant difference between women with Paget's disease and the rate of cancer in that demographic group (Preti 2003).
Wilkinson and Brown subclassified Paget's disease of the vulva into primary or secondary disease (Wilkinson 2002). Primary Paget's disease is of vulval cutaneous origin, and secondary vulval Paget's disease is due to a non‐cutaneous neoplasm, often of adjacent sites.
Description of the intervention
Surgery can involve local excision, radical excision or vulvectomy. Margins often extend outside the clinically abnormal area, so some studies suggest frozen section or preoperative mapping biopsies to delineate the margins of excision. Other interventions include topical imiquimod (an immune response modifier), radiotherapy, chemotherapy, photodynamic therapy (topical and systemic) and laser therapy, or a combination of these approaches. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery.
How the intervention might work
Surgery removes the abnormal area. Disease tends to be multifocal, and complete eradication is not guaranteed. Surgical excision can also cause significant vulval mutilation, with consequent psychological morbidity (Tsutsumida 2003). Photodynamic therapy works by the exposure of sensitised cells to a specific wavelength of light, which activates a cascade of photochemical and photobiological events, causing irreversible damage to tumour tissue (Shieh 2002). Radiotherapy destroys tissues by damaging deoxyribonucleic acid (DNA), affecting normal as well as abnormal tissues. Chemotherapy has been used alone or in conjunction with radiotherapy. Topical imiquimod, usually a 5% cream, is an immune response modifier that induces high levels of interferon, although the complete mechanism of action is complex and not fully understood. It causes inflammation, which in some cases can be poorly tolerated (Woodmansee 2006). Carbon dioxide (CO2) laser has been used in other vulval conditions, such as vulval intraepithelial neoplasia (Maclean 1995), since the 1970s and was initially used for treatment of disease of the cervix. The depth of destruction can be controlled and planned, but needs to be deep enough to decrease the likelihood of recurrence.
Why it is important to do this review
Paget's disease is a rare condition, and there is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations and mutilation of the vulva. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and we considered that it was important to evaluate the available evidence. Paget's disease most commonly occurs in elderly women, and having evidence‐based alternative treatments to surgery would be of benefit to these women.
Objectives
To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva.
Methods
Criteria for considering studies for this review
Types of studies
We wanted to include randomised controlled trials (RCTs). However, since RCTs were unlikely, we also searched for non‐randomised studies with concurrent comparison groups:
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quasi‐randomised trials;
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non‐randomised trials;
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prospective and retrospective cohort studies;
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case series of 10 or more women.
We excluded case‐controlled studies, uncontrolled observational studies and case series of fewer than 10 women.
In order to minimise selection bias if no RCTs were identified, we only included studies that used statistical adjustment for baseline case mix using multivariable analyses (e.g. disease severity, age, co‐morbidity, previous treatment).
Types of participants
Adult women (aged 18 years or older) with biopsy‐confirmed Paget's disease. We applied no exclusion criteria.
Types of interventions
We searched for all interventions used in Paget's disease. The mainstay of treatment is surgery, which is either conservative or radical.
Other interventions that are used include: radiotherapy; topical treatments, including steroids; photodynamic therapy; imiquimod; systemic treatments, including chemotherapeutic agents and any treatment combinations. We considered comparisons of any two treatment modalities.
Types of outcome measures
We did not use outcome measures as part of the inclusion criteria.
Primary outcomes
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Overall survival. Survival was assessed from the time when women were enrolled in the study.
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Disease‐free survival. Defined as the documented time between treatment and confirmed recurrence.
Secondary outcomes
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Quality of life (QoL), measured using a validated scale.
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Adverse events classified according to CTCAE 2006:
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direct surgical morbidity;
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surgically related systemic morbidity;
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delayed (hospital) discharge and recovery;
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toxicity of photodynamic therapy;
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radiotherapy toxicity;
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chemotherapy toxicity.
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Toxicity was grouped as:
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haematological;
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gastrointestinal;
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genitourinary;
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skin;
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neurological;
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pulmonary.
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Search methods for identification of studies
Electronic searches
We searched the following electronic databases:
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the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register to September 2013;
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the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 7, 2013;
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MEDLINE (from 1948 to September 2013);
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EMBASE (from 1980 to September 2013).
The CENTRAL, MEDLINE and EMBASE search strategies are presented in Appendix 1, Appendix 2 ad Appendix 3, respectively.
We identified all relevant articles on PubMed and, using the 'related articles' feature, we carried out a further search for newly published articles.
Searching other resources
We searched:
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the online bibliography of Paget's disease (www.tiny.cc/PagetsOnline) set up by the Oxford University library service;
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metaRegister, Physicians Data Query, www.controlled‐trials.com/rct, www.clinicaltrials.gov and www.cancer.gov/clinicaltrials for ongoing studies;
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conference proceedings and abstracts through ZETOC (zetoc.mimas.ac.uk) and WorldCat Dissertations.
Handsearching
We handsearched and checked the citation lists of included studies, key textbooks and previous systematic reviews. We handsearched reports of the following conferences:
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Annual Meeting of the American Society of Gynaecologic Oncologist;
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Annual Meeting of the International Gynaecologic Cancer Society;
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British Cancer Research Meeting;
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Annual Meeting of European Society of Medical Oncology;
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Annual Meeting if the American Society of Clinical Oncology;
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British Society for the study of Vulval Disease;
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International Society for the Study of Vulvo‐Vaginal Disease;
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European College for the Study of Vulval Disease.
Data collection and analysis
Selection of studies
We downloaded all titles and abstracts retrieved by electronic searching to the reference management database Endnote. We removed duplicates and two review authors (KE, JM) independently examined the remaining references. We excluded studies that clearly did not meet the inclusion criteria and obtained copies of the full text of potentially relevant references. Two review authors (KE, EA) independently assessed the eligibility of the retrieved papers and resolved any disagreements by discussion. When necessary, a third review author (SC or AB) participated in discussions. We documented reasons for exclusions. We excluded all articles that we retrieved, as they did not meet the inclusion criteria. We did not identify any studies that met our inclusion criteria from our searches of the grey literature. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease (See Effects of interventions for studies, which included at least 10 women and Agreements and disagreements with other studies or reviews for a general discussion of a wider range of studies and reviews).
In future updates of the review, we will use the above methodology and the methods described in Differences between protocol and review.
Results
Description of studies
Results of the search
The search strategy identified 635 separate references by title and abstracts. Two review authors (KE, JM) sifted through these and excluded abstracts that did not include at least 10 women with Paget's disease of the vulva and then applied the other inclusion criteria. Where the contents of the paper were not clear from the abstract, we obtained the full‐text papers in order to be rigorous in the searching. We identified 31 references that reported on 30 studies that potentially met the inclusion criteria. We excluded all studies after inspection of the full papers.
Two review authors (KE, JM) independently searched the grey literature and did not identify any relevant studies. All studies were at a high risk of bias and retrospective in nature.
Included studies
None of the studies met our inclusion criteria and we excluded them all from the review. However, 20 studies were included in a narrative discussion in Effects of interventions. All the studies were retrospective data analyses, the earliest women included was diagnosed in 1939. Across the studies, the age range was 35 to 100 years, but there were minimal other demographic data available due to the retrospective nature of the data collection. There were 581 women included with some data for analysis. The most common surgery was a wide local excision (n = 202; 35%) and radical vulvectomy (n = 157; 27%). In total, 135 women had a simple vulvectomy, 48 women had a hemivulvectomy and one woman had a skinning vulvectomy. Ultracision was used to treat one woman, primary chemotherapy was used in seven cases, primary radiotherapy in 14 cases and laser therapy was in 23 cases. Two women undergoing surgery had been treated with neoadjuvant radiotherapy. Treatment regimens for radiotherapy and chemotherapy were not clearly documented in any of the papers, and, therefore, further discussion will focus on the surgical management.
Although some women received treatments in addition to surgery, all 20 studies discussed contained women having a variety of surgical interventions, ranging from wide excisions to radical vulvectomies. Case series ranged from 10 to 100 women. Data were variable between the papers; some contained limited clinical data because the main focus was discussion of pathology. Forty of the 306 women across all the studies had a cancer at another site, although 10 of these were definitely metachronus, and for many it was unclear. They are described in greater detail in Table 1.
| Study | Methods | Participants | Intervention | Outcomes | Notes |
| Retrospective review of records 1996‐2005 | 11 women with Paget's disease of the vulva' from 1 centre in Athens. Median age 64 years (range 53 to 75) | Ultracision, SV, RV with groin node dissection | All had topical steroid use before diagnosis. 1/11 had ultracision, 7/11 had SV, 3/11 had radical surgery. All had FSs (10/11 margins negative at FS, 9/11 negative at final pathology). 3/11 had a recurrence, 1/1 who had ultracision, 1/7 with SV, 1/3 with RV. 2/2 with positive margins | 1 had concurrent breast cancer | |
| Retrospective review from pathology database | 28 women with Paget's disease of the vulva', median age 68 years, range 48 to 86. | RV, SV, WLE | 3/28 had RV, 18/28 had SV, 7/28 had WLE. 14/20 with positive margins recurred, 3/8 with negative margins recurred. 14/17 further surgery, 1/17 treated with Retin‐A | 11 women had a secondary malignancy | |
| Retrospective data collection, time period not defined | 21 women with diagnosis of Paget's disease of the vulva' | WLE, hemivulvectomy, RV | WLE 13, hemivulvectomy 2, RV 5. 1 woman had biopsies only. Margins not documented by type of surgery. 13/20 had positive margins, 1/7 recurrence with negative margins, 7/13 recurrence with positive margins | 2 women died of other malignancies, 1 died from CVA after hip surgery, 1 died of metastatic Paget's | |
| Retrospective data 1939‐1987 | 31 women, age range 49‐84 years with a histological diagnosis of Paget's disease of the vulva' | WLE, vulvectomy or skinning vulvectomy, RV | 4 had WLE, 22 had vulvectomy and 3 had a RV. 1 woman had a skinning vulvectomy. Out of 28 women, 14 had negative margins, 8 had positive margins, 6 were not documented. 3/14 with positive margins recurred, 2/8 with negative margins recurred | No mortality. 5 adenocarcinomas excluded | |
| Retrospective data 1962‐1996 Multiple institutions | 100 women with Paget's disease of the vulva'. Age range 35‐100 years | RV with or without node dissection, radical hemivulvectomy, WLE | 58 radical vulvectomies, 10 radical hemivulvectomies, 32 WLE. Recurrence 18/58 radical, 2/10 hemivulvectomy, 14/32 WLE. Median time to recurrence 3 years. Not able to assess margins in this study as retrospective. 4 women had an adenoca at resection | 1 woman DoD | |
| Retrospective review 1969‐1987 | 19 women with Paget's disease of the vulva' mean age 65.2 years, range 44‐81 | WLE, SV, hemivulvectomy, RV | 4/19 WLE, 9/19 SV, 2/19 hemivulvectomy, 4/19 RV. 9/19 recurred, 1 DoD. 8/9 recurrences treated surgically 1 treated with laser and 5 5‐FU. 2/4 WLE recurred, 5/9 SV recurred, 1/2 hemivulvectomy recurred, 1/4 RV recurred | 5 had an associated malignancy. No comment on margin status | |
| Retrospective review and re‐review of all histology 1982 to 1993 | 14 women from 1 centre with known Paget's disease of the vulva'. Mean age 70.5 years, range 57‐83 | WLE, SV, modified RV | 8/14 WLE, 3/14 SV, 3/14 modified RV. 2/5 with positive margins recurred, 3/9 with negative margins recurred. After clinical judgement of negative margins, 6/17 were positive at final pathology. After FS, 3/8 that were negative at FS were positive at final pathology. No difference between FS and inspection (P value = 1). 2/8 having a WLE recurred, 1/3 having a SV recurred, 2/3 having a modified RV recurred | 7 women had a metachronus cancer | |
| Retrospective review from 1 centre | 19 women with Paget's disease of the vulva', median age 65 years, range 56‐86 | SV, RV, RV + groin node dissection | 13/19 SV, 4/19 RV, 2/19 RV + groin node dissection. 4/13 recurrences in SV group, 1/4 recurrences in RV. Minimal invasion had no effect on recurrence or prognosis; 2/7 minimally invasive recurred compared with 3/7 intraepithelial (5 were initially invasive) | No comment on margin status | |
| Retrospective data 1940‐1976 | 13 women with confirmed Paget's disease of the vulva. Median age 65 years, range 38‐86 | SV, RV, radiotherapy | 8/13 SV, 4/13 RV. 2 had pre‐surgical radiotherapy. 1/8 recurrence after SV, 1/4 re‐excision for positive margins after RV, 2/4 recurrences with RV but all free of disease after re‐excision | 4 had other cancers, 3 deaths of other causes | |
| Retrospective data 1990‐2009 | 14 women with diagnosis of Paget's disease of the vulva'. Mean age 54.3 years, range 29‐72 | Hemivulvectomy, WLE, RV | 2/14 hemivulvectomy, 5/14 WLE, 7/14 RV. Positive margins in 8/14. 3/8 recurrences with positive margins, 2/6 recurrences with negative margins | Recurrences treated with radiotherapy | |
| Retrospective review of patient records | 52 women with biopsy‐confirmed Paget's disease of the vulva. Mean age 67 years, range 39‐94 | Surgery, surgery + laser therapy, laser therapy alone | 31 had surgery alone, 7 recurrences at 1 year (23%); 15 had surgery + laser therapy with 5 recurring within 1 year (33%); 6 had laser therapy alone with 4 recurrences at 1 year (67%) | Treatment was chosen by size of lesion so the largest lesions had laser therapy, so the survival rate may be related to disease rather than treatment | |
| Retrospective data 1976‐1990 | 36 women age range 45‐91 years with a histological diagnosis of Paget's disease of the vulva | Local excision, partial vulvectomy or RV | 29 women followed‐up. 11 vulvectomies; 4 involved margins, 2/4 recurred. 4 clear margins, 3/4 recurred.14 partial vulvectomies; 12 involved margins, 3/12 recurred. 1 clear margin, 1/1 recurred. 4 local excisions, all clear margins 2/4 recurred. Others margins not known. Altogether 11/29 recurrences, 5/16 with positive margins, 5/9 with negative margins | 3 died of associated malignancy | |
| Retrospective data 1986‐2005 | 22 women with Paget's disease of the vulva. Mean age 71.5 years, range 51‐85 | SV, RV + groin node dissection, chemotherapy (cisplatin and 5‐FU) | 18 SV, 3 RV, 1 primary chemotherapy (stage 4 disease) dead of disease after 12/12. 3/18 SV had positive margins; 2 treated with etoposide, 1 with radiotherapy. 2/3 RV positive margins; 1 treated with radiotherapy, 1 with MEP. Only 1 recurrence in whole series (RV + MEP) | 2 associated malignancies | |
| Retrospective data 1944‐1997 | 76 women with a diagnosis of Paget's disease of the vulva, mean age 67.5 years | 6 women had chemotherapy, 12 had radiotherapy. 20 had WLE, 26 had SV, 20 had RV, 2 had no treatment | 53% having surgery had positive margins, 23% negative, 26% unknown. Recurrence was 31% in those with positive margins, 33% in those with negative margins | 16% DoD. Exact chemotherapy used not documented | |
| Retrospective review 1995‐2000 | 10 women in 1 institution with Paget's disease of the vulva, mean age 58 years, range 46‐84 | WLE, RV and bilateral groin node dissection | 8/10 WLE, 2/10 RV; 2/8 recurrences with WLE, 1/2 recurrences with radical surgery. No comment on margins | 2 women previously treated before treatment in the centre | |
| Retrospective data review of all particitants with extramammary Paget's disease | 25/33 participants had Paget's disease of the vulva'. Median age 70 years | Local excision, hemivulvectomy, radiotherapy | 5/25 local excision, 18/25 hemivulvectomy, 2/25 radiotherapy. 10/25 recurred; 2/5 local excisions, 8/18 hemivulvectomy, 0/2 radiotherapy. Margin status not broken down for tumour type. No radical surgery | No perioperative mortality or disease‐related mortality | |
| Retrospective review 1996‐2008 | 11 women with histologically verified Paget's disease of the vulva, mean age 66.6 years, range 52‐77 | WLE, RV, SV | 7/11 WLE, 2/11 SV, 2/11 RV. 6/11 recurred; 4/8 with positive margins, 2/3 with negative margins. 4/7 with WLE, 0/2 with SV, 2/2 with RV. 4/6 recurrences had further excisions with no further disease, 1 had photodynamic therapy and was alive with disease, 1 declined treatment and died of disease | No surgical mortality/morbidity. 1 DoD. 3 had previous cancers 3‐15 years before diagnosis of Paget's | |
| Retrospective | 56 women with known diagnosis of Paget's of the vulva. Mean age 69 years, range 42‐89 | WLE, SV, partial vulvectomy, RV, laser ablation | Surgical extent did not affect recurrence rate. 11/37 recurrences in those with conservative surgery, 5/16 recurrences with radical surgery, 2/2 recurrences with laser ablation. 6 women received adjuvant radiotherapy; 1 died of disease, 5 had no further recurrences. 32% recurrence rate. 20/30 with positive margins recurred, 3/17 with negative margins recurred | Currently 43% no evidence of disease | |
| Retrospective data 1975‐1984 | 13 women with biopsy‐ confirmed Paget's disease of the vulva or anus. Women with anal disease excluded for this review; data from 10 women' analysed. Age range 45‐81 years | SV, RV | 9 simple vulvectomies, 1 RV. FS showed positive margins in 4/8. 2 had positive margins on final specimens with no FS, 1 had re‐excision, 1 no re‐excision and no recurrence. All free of disease in follow‐up | ‐ | |
| Retrospective data 1988‐2000 | 23 women with Paget's disease of the vulva, age range 46‐84 years' | WLE, and if adenoca present proceed to RV and node dissection | 17 WLE, 6 radical resections. 13 women with negative FS margins, 6 of these had positive margins in final resection. 2/17 with negative margins recurred, 6/16 with positive margins recurred. Mean time to recurrence 30 months. 2/6 with radical resections recurred, 6/17 with conservative surgery recurred. All those with invasive disease had a radical resection | 5 women (22%) had other primary cancers all treated previously |
5‐FU: fluorouracil; CVA: cerebrovascular accident; DoD: dead of disease; FS: frozen section; MEP: mitomycin + etoposide + cisplatin; RV: radical vulvectomy; SV: simple vulvectomy; WLE: wide local excision.
All studies were from large hospitals in Europe and Northern America, reporting from retrospective reviews of patient and histopathological records. Few information were available in the studies regarding patient demographics although all reported age.
Excluded studies
We excluded 30 references after obtaining the full text paper for the following reasons.
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Twenty references reported on studies that did not use statistical adjustment to reduce the risk of selection bias (Bakalianou 2008; Black 2007; Crawford 1999; Curtin 1990; Fanning 1999; Feuer 1990; Fishman 1995; Goldblum 1997; Lee 1977; Lee 2010; Louis‐Sylvestre 2001; Molinie 1993; Niikura 2006; Parker 2000; Petkovic 2006; Pierie 2003; Roh 2010; Shaco‐Levy 2010; Stacy 1986; Tebes 2002). We discussed all of these studies further.
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One study only included eight women with Paget's disease (two with melanoma) (Koss 1968), and two studies included just seven women with full information (Parmley 1975; Tanaka 2009). Another contained three cases of Paget's diseases only (Strempel 1958).
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Three references reported case reports only (Martorell‐Calatayud 2009; Wang 2003; Zawislak 2004), and one contained only one women with Paget's disease in a study on carcinoma of the vulva (Shingleton 1970).
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Two references were not available through any UK source, including the British Library and we have excluded them from the review (Lu 1999; Shrestha 2010). We will continue search for full‐text copies for completeness of the review and to reduce possibility of biases.
For further details of all the excluded studies, see Table 1 and the Characteristics of excluded studies table.
Risk of bias in included studies
No studies met our inclusion criteria and we excluded them all from the review. We did, however, report some results in a narrative discussion in the Effects of interventions section. These studies were retrospective case series and were at a high risk of bias, although we did not objectively and subjectively assess this since they did not meet the inclusion criteria.
Effects of interventions
None of the studies used any statistical adjustment for baseline case mix using multivariable analyses. The number of included women in most of the studies was low, which may account for the lack of statistical adjustment. We have presented the main results of the studies but have not made any inferences due to the problem of selection bias and fact that all studies were at a high risk of bias.
The 20 studies discussed here met all the inclusion criteria, except having any statistical adjustment to decrease the risk of bias. Any meta‐analysis, therefore, would be invalid, but their results warrant discussion.
Data on survival were available from eight studies (Crawford 1999; Curtin 1990; Fanning 1999; Lee 1977; Molinie 1993; Parker 2000; Pierie 2003; Roh 2010). These included information on 306 women and reported 23 deaths. There were 14 deaths related to disease, five deaths from other malignancies and four deaths related to other causes. Since nearly all treatment in the studies was surgical, we cannot comment on mortality to treatment modality. Two series used chemotherapy as a first‐line treatment (Niikura 2006; Parker 2000). One woman in the Niikura 2006 study was given chemotherapy for stage IV disease, and they died of disease. The chemotherapy used was cisplatin plus fluorouracil. Six women out of 76 (8%) in the Parker 2000 study had chemotherapy as the primary treatment. However, in this study there was no documentation regarding what chemotherapy regimens were used, or how women were selected for chemotherapy. In this series of women, chemotherapy was associated with poor prognosis with regards to survival, compared with other treatment, but this is likely to be due to selection bias, and this difference cannot be expanded any further due to the small series and lack of detailed information. In this same study (Parker 2000), 12 women were also treated with primary radiotherapy (16%), although again there was no documentation of treatment regimens, and whether doses used were of palliative or radical levels. Survival was again shown to be worse after radiotherapy, but the same caveats apply as to their comments on chemotherapy.
The largest series of laser therapy included six women having laser alone and 15 women having a combination of laser and surgery (Louis‐Sylvestre 2001). The recurrence rates for the small number of women having laser alone were very high (67% at one year), but laser alone was only used in women with large, likely inoperable lesions, so it is not possible to draw conclusions regarding the efficacy of the treatment.
Radiotherapy was used as a first‐line treatment in only four women across all the other papers. With these small numbers, it is not possible to form any conclusions as to its effectiveness as a treatment. With the data available in the studies, it is also not possible to draw any conclusions with regards to disease‐free survival, as, due to the nature of retrospective series, there is not adequate information with which to categorise recurrences.
The studies contained variable length of follow‐up, varying from nine months up to 38 years. Accurate survival data were not possible given the number of women followed up for fewer than five years. Of the 40 women across all the studies who had a confirmed malignancy at another site (13%), at least 10 of these were metachronus and treated before the presentation of Paget's of the vulva. It is not possible from the data in the studies to define clearly the number of secondary Paget's included.
Margin status
Margin status of the initial specimens after surgery were known and clearly documented in 13 out of the 19 studies. Due to the small numbers in each series, most papers favoured the margin status making no difference to chance of recurrence. However, with the small numbers involved, inferences should not be made as to the risk of recurrence based on margin status in these women. Out of the 529 women in the 19 studies, margin status and recurrence data were known in 307, although follow‐up length was variable, from months to more than 20 years. This highlights the difficulties of extracting meaningful information from data collected retrospectively, when in these studies, margin status was only known in 57% of women.
Radical versus conservative surgery
The exact surgery performed is described in different ways in different studies. Wide local excision, hemi‐vulvectomy, simple vulvectomy and radical vulvectomy sometimes with groin node dissection are the most common. It could be assumed that the more radical the surgery, the larger the lesion, but these data are not possible to extract from the papers. None of the study authors described in detail the surgery undertaken for women in their study. Tebes 2002 states that all those with invasive disease had radical surgery, but this does not apply to other studies. In all of the studies, almost twice as many women had conservative surgery than radical. It seems reasonable that surgery should be tailored to the size of the lesion, and radical surgery to be used only when necessary to obtain clear margins.
Discussion
Summary of main results
We did not identify any studies that met our inclusion criteria. Consequently, there is no evidence from this review as to which treatment modality is most effective and safe in the Paget's disease of the vulva. We were able to review the results of 20 studies in detail that reported on at least 10 women with biopsy‐confirmed Paget's disease of the vulva. We were unable to make any comparisons between treatment modalities, due to minimal numbers of women having non‐surgical treatment. Due the variation in the radicality of the surgery itself, we cannot make any inferences about disease recurrence.
Overall completeness and applicability of evidence
At the outset of this review, we were aware, due to the rare nature of Paget's disease of the vulva, that accumulation of helpful outcome data would be difficult. We set a cut‐off of series with at least 10 women, in order to try to include as much of the published data as possible, while excluding case reports and very small case series. The accumulation of meaningful data on rare diseases remains challenging, but is a vital part of extending our knowledge base on rare conditions.
It was noticeable that the majority of published data is now relatively old (10 out of 20 studies were pre‐2000) and there was no published prospective data collection. This meant that it was not possible to gain any evidence regarding morbidity from these papers, as morbidity data need to be collected prospectively. Other flaws in retrospective data collection include a lack of clarity in decision making regarding choices of surgery and whether any other treatment options had been offered or discussed.
We have specifically reviewed only women with Paget's disease of the vulva. There is evidence that may be available for perianal disease or scrotal disease in men that may be appropriate to guide treatment.
Quality of the evidence
There is no available evidence of adequate quality; selected retrospective studies formed the only available evidence base and are the best that is available currently in the literature, but these study designs are significantly flawed. While taking into account the inherent problems with these data, the way forward is to collect prospective data on all treatments for Paget's disease of the vulva, ideally as a national database, in order that clear outcome and morbidity data, as well as patient satisfaction data can be collected.
Potential biases in the review process
Due to the retrospective nature of all the studies, there are no morbidity data available, or patient satisfaction analysis, and, therefore, no comment can be made on QoL between treatments. This is significant when considering radical surgery, and re‐excision after previous surgery. Selection bias is challenging when dealing with retrospective studies, when radicality of treatment would be dependent on surgeon choice. Most of the women in the studies had treatment before the advent of the multidisciplinary team, and, therefore, alternative treatments to surgery may not have been available, or not considered. It was not possible to extract this information from the studies.
Agreements and disagreements with other studies or reviews
There are no other systematic reviews of Paget's disease of the vulva. Our initial search strategy included several case reports of successful treatment with 5% imiquimod in, eight women (Bertozzi 2009; Hatch 2008; Sendagorta 2010; Tonguc 2011; Wang 2003). Other treatments that have been used and published as case reports include laser ablation (Valentine 1992), primary curative intent radiotherapy (Luk NM 2003; Moreno‐Arias 2003), and photodynamic therapy (Raspagliesi 2006, which was a pilot study of six women, but with no control group). Nardelli carried out a review into photodynamic therapy for mammary and extramammary Paget's disease (Nardelli 2011). It contained 23 studies, but nine were single case reports only. The largest study included only two women with Paget's disease of the vulva (Li 2010). These data were collected prospectively, but neither woman had a complete response. Across all Paget's disease, this non‐systematic review concluded that evidence was limited, and most women across all studies and Paget's sites had follow‐up of one year or less.
The published literature regarding treatment of Paget's disease of the vulva is dominated by surgical treatment. This is likely to be due to the nature of the published studies, which are retrospective series of women who have undergone surgery, rather than a proper cohort. However, there is also no evidence for surgery as a treatment of Paget's disease of the vulva, and currently any treatment is not based on evidence, but on empirical reasoning.
| Study | Methods | Participants | Intervention | Outcomes | Notes |
| Retrospective review of records 1996‐2005 | 11 women with Paget's disease of the vulva' from 1 centre in Athens. Median age 64 years (range 53 to 75) | Ultracision, SV, RV with groin node dissection | All had topical steroid use before diagnosis. 1/11 had ultracision, 7/11 had SV, 3/11 had radical surgery. All had FSs (10/11 margins negative at FS, 9/11 negative at final pathology). 3/11 had a recurrence, 1/1 who had ultracision, 1/7 with SV, 1/3 with RV. 2/2 with positive margins | 1 had concurrent breast cancer | |
| Retrospective review from pathology database | 28 women with Paget's disease of the vulva', median age 68 years, range 48 to 86. | RV, SV, WLE | 3/28 had RV, 18/28 had SV, 7/28 had WLE. 14/20 with positive margins recurred, 3/8 with negative margins recurred. 14/17 further surgery, 1/17 treated with Retin‐A | 11 women had a secondary malignancy | |
| Retrospective data collection, time period not defined | 21 women with diagnosis of Paget's disease of the vulva' | WLE, hemivulvectomy, RV | WLE 13, hemivulvectomy 2, RV 5. 1 woman had biopsies only. Margins not documented by type of surgery. 13/20 had positive margins, 1/7 recurrence with negative margins, 7/13 recurrence with positive margins | 2 women died of other malignancies, 1 died from CVA after hip surgery, 1 died of metastatic Paget's | |
| Retrospective data 1939‐1987 | 31 women, age range 49‐84 years with a histological diagnosis of Paget's disease of the vulva' | WLE, vulvectomy or skinning vulvectomy, RV | 4 had WLE, 22 had vulvectomy and 3 had a RV. 1 woman had a skinning vulvectomy. Out of 28 women, 14 had negative margins, 8 had positive margins, 6 were not documented. 3/14 with positive margins recurred, 2/8 with negative margins recurred | No mortality. 5 adenocarcinomas excluded | |
| Retrospective data 1962‐1996 Multiple institutions | 100 women with Paget's disease of the vulva'. Age range 35‐100 years | RV with or without node dissection, radical hemivulvectomy, WLE | 58 radical vulvectomies, 10 radical hemivulvectomies, 32 WLE. Recurrence 18/58 radical, 2/10 hemivulvectomy, 14/32 WLE. Median time to recurrence 3 years. Not able to assess margins in this study as retrospective. 4 women had an adenoca at resection | 1 woman DoD | |
| Retrospective review 1969‐1987 | 19 women with Paget's disease of the vulva' mean age 65.2 years, range 44‐81 | WLE, SV, hemivulvectomy, RV | 4/19 WLE, 9/19 SV, 2/19 hemivulvectomy, 4/19 RV. 9/19 recurred, 1 DoD. 8/9 recurrences treated surgically 1 treated with laser and 5 5‐FU. 2/4 WLE recurred, 5/9 SV recurred, 1/2 hemivulvectomy recurred, 1/4 RV recurred | 5 had an associated malignancy. No comment on margin status | |
| Retrospective review and re‐review of all histology 1982 to 1993 | 14 women from 1 centre with known Paget's disease of the vulva'. Mean age 70.5 years, range 57‐83 | WLE, SV, modified RV | 8/14 WLE, 3/14 SV, 3/14 modified RV. 2/5 with positive margins recurred, 3/9 with negative margins recurred. After clinical judgement of negative margins, 6/17 were positive at final pathology. After FS, 3/8 that were negative at FS were positive at final pathology. No difference between FS and inspection (P value = 1). 2/8 having a WLE recurred, 1/3 having a SV recurred, 2/3 having a modified RV recurred | 7 women had a metachronus cancer | |
| Retrospective review from 1 centre | 19 women with Paget's disease of the vulva', median age 65 years, range 56‐86 | SV, RV, RV + groin node dissection | 13/19 SV, 4/19 RV, 2/19 RV + groin node dissection. 4/13 recurrences in SV group, 1/4 recurrences in RV. Minimal invasion had no effect on recurrence or prognosis; 2/7 minimally invasive recurred compared with 3/7 intraepithelial (5 were initially invasive) | No comment on margin status | |
| Retrospective data 1940‐1976 | 13 women with confirmed Paget's disease of the vulva. Median age 65 years, range 38‐86 | SV, RV, radiotherapy | 8/13 SV, 4/13 RV. 2 had pre‐surgical radiotherapy. 1/8 recurrence after SV, 1/4 re‐excision for positive margins after RV, 2/4 recurrences with RV but all free of disease after re‐excision | 4 had other cancers, 3 deaths of other causes | |
| Retrospective data 1990‐2009 | 14 women with diagnosis of Paget's disease of the vulva'. Mean age 54.3 years, range 29‐72 | Hemivulvectomy, WLE, RV | 2/14 hemivulvectomy, 5/14 WLE, 7/14 RV. Positive margins in 8/14. 3/8 recurrences with positive margins, 2/6 recurrences with negative margins | Recurrences treated with radiotherapy | |
| Retrospective review of patient records | 52 women with biopsy‐confirmed Paget's disease of the vulva. Mean age 67 years, range 39‐94 | Surgery, surgery + laser therapy, laser therapy alone | 31 had surgery alone, 7 recurrences at 1 year (23%); 15 had surgery + laser therapy with 5 recurring within 1 year (33%); 6 had laser therapy alone with 4 recurrences at 1 year (67%) | Treatment was chosen by size of lesion so the largest lesions had laser therapy, so the survival rate may be related to disease rather than treatment | |
| Retrospective data 1976‐1990 | 36 women age range 45‐91 years with a histological diagnosis of Paget's disease of the vulva | Local excision, partial vulvectomy or RV | 29 women followed‐up. 11 vulvectomies; 4 involved margins, 2/4 recurred. 4 clear margins, 3/4 recurred.14 partial vulvectomies; 12 involved margins, 3/12 recurred. 1 clear margin, 1/1 recurred. 4 local excisions, all clear margins 2/4 recurred. Others margins not known. Altogether 11/29 recurrences, 5/16 with positive margins, 5/9 with negative margins | 3 died of associated malignancy | |
| Retrospective data 1986‐2005 | 22 women with Paget's disease of the vulva. Mean age 71.5 years, range 51‐85 | SV, RV + groin node dissection, chemotherapy (cisplatin and 5‐FU) | 18 SV, 3 RV, 1 primary chemotherapy (stage 4 disease) dead of disease after 12/12. 3/18 SV had positive margins; 2 treated with etoposide, 1 with radiotherapy. 2/3 RV positive margins; 1 treated with radiotherapy, 1 with MEP. Only 1 recurrence in whole series (RV + MEP) | 2 associated malignancies | |
| Retrospective data 1944‐1997 | 76 women with a diagnosis of Paget's disease of the vulva, mean age 67.5 years | 6 women had chemotherapy, 12 had radiotherapy. 20 had WLE, 26 had SV, 20 had RV, 2 had no treatment | 53% having surgery had positive margins, 23% negative, 26% unknown. Recurrence was 31% in those with positive margins, 33% in those with negative margins | 16% DoD. Exact chemotherapy used not documented | |
| Retrospective review 1995‐2000 | 10 women in 1 institution with Paget's disease of the vulva, mean age 58 years, range 46‐84 | WLE, RV and bilateral groin node dissection | 8/10 WLE, 2/10 RV; 2/8 recurrences with WLE, 1/2 recurrences with radical surgery. No comment on margins | 2 women previously treated before treatment in the centre | |
| Retrospective data review of all particitants with extramammary Paget's disease | 25/33 participants had Paget's disease of the vulva'. Median age 70 years | Local excision, hemivulvectomy, radiotherapy | 5/25 local excision, 18/25 hemivulvectomy, 2/25 radiotherapy. 10/25 recurred; 2/5 local excisions, 8/18 hemivulvectomy, 0/2 radiotherapy. Margin status not broken down for tumour type. No radical surgery | No perioperative mortality or disease‐related mortality | |
| Retrospective review 1996‐2008 | 11 women with histologically verified Paget's disease of the vulva, mean age 66.6 years, range 52‐77 | WLE, RV, SV | 7/11 WLE, 2/11 SV, 2/11 RV. 6/11 recurred; 4/8 with positive margins, 2/3 with negative margins. 4/7 with WLE, 0/2 with SV, 2/2 with RV. 4/6 recurrences had further excisions with no further disease, 1 had photodynamic therapy and was alive with disease, 1 declined treatment and died of disease | No surgical mortality/morbidity. 1 DoD. 3 had previous cancers 3‐15 years before diagnosis of Paget's | |
| Retrospective | 56 women with known diagnosis of Paget's of the vulva. Mean age 69 years, range 42‐89 | WLE, SV, partial vulvectomy, RV, laser ablation | Surgical extent did not affect recurrence rate. 11/37 recurrences in those with conservative surgery, 5/16 recurrences with radical surgery, 2/2 recurrences with laser ablation. 6 women received adjuvant radiotherapy; 1 died of disease, 5 had no further recurrences. 32% recurrence rate. 20/30 with positive margins recurred, 3/17 with negative margins recurred | Currently 43% no evidence of disease | |
| Retrospective data 1975‐1984 | 13 women with biopsy‐ confirmed Paget's disease of the vulva or anus. Women with anal disease excluded for this review; data from 10 women' analysed. Age range 45‐81 years | SV, RV | 9 simple vulvectomies, 1 RV. FS showed positive margins in 4/8. 2 had positive margins on final specimens with no FS, 1 had re‐excision, 1 no re‐excision and no recurrence. All free of disease in follow‐up | ‐ | |
| Retrospective data 1988‐2000 | 23 women with Paget's disease of the vulva, age range 46‐84 years' | WLE, and if adenoca present proceed to RV and node dissection | 17 WLE, 6 radical resections. 13 women with negative FS margins, 6 of these had positive margins in final resection. 2/17 with negative margins recurred, 6/16 with positive margins recurred. Mean time to recurrence 30 months. 2/6 with radical resections recurred, 6/17 with conservative surgery recurred. All those with invasive disease had a radical resection | 5 women (22%) had other primary cancers all treated previously | |
| 5‐FU: fluorouracil; CVA: cerebrovascular accident; DoD: dead of disease; FS: frozen section; MEP: mitomycin + etoposide + cisplatin; RV: radical vulvectomy; SV: simple vulvectomy; WLE: wide local excision. | |||||
