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Background:
Systematic Review

Vulvar Paget’s Disease: A Systematic Review of the MITO Rare Cancer Group

by
Giuseppe Caruso
1,2,
Amelia Barcellini
3,4,
Roberta Mazzeo
5,*,
Roberta Gallo
1,
Maria Giuseppa Vitale
6,
Anna Passarelli
7,
Giorgia Mangili
8,
Sandro Pignata
7 and
Innocenza Palaia
1
1
Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Policlinico Umberto I, 00161 Rome, Italy
2
Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I, 00161 Rome, Italy
3
Radiation Oncology Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, 27100 Pavia, Italy
4
Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy
5
Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
6
Department of Oncology and Hematology, University Hospital of Modena, 41100 Modena, Italy
7
Department of Urology and Gynecology, Istituto Nazionale Tumori IRCSS, “Fondazione G. Pascale”, 80131 Naples, Italy
8
Obstetrics and Gynecology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(6), 1803; https://doi.org/10.3390/cancers15061803
Submission received: 4 January 2023 / Revised: 7 March 2023 / Accepted: 14 March 2023 / Published: 16 March 2023
(This article belongs to the Special Issue Rare Gynecological Cancers)
Browse Figure
Review Reports Versions Notes

Abstract

:

Simple Summary

Vulvar Paget’s disease (VPD) is an extremely rare malignancy of the vulva with a high local recurrence rate and low mortality. Due to its non-specific symptoms and lack of clinical knowledge, VPD is often misdiagnosed with eczematous skin lesions, and the definitive diagnosis is often delayed. Since currently there is no global consensus on the optimal management of VPD, we present here a systematic review aiming to give readers a concise overview of the state-of-the-art evidence and the emerging therapeutic opportunities.

Abstract

Vulvar Paget’s disease (VPD) is a rare form of cutaneous adenocarcinoma of the vulva, which accounts for about 1–2% of all vulvar neoplasms and mainly affects post-menopausal women. The clinical presentation is usually non-specific and mimics chronic erythematous skin lesions; therefore, the diagnosis is often difficult and delayed. Although VPD is typically diagnosed at a locally advanced stage and has a high recurrence rate, the prognosis is overall favorable with a 5-year survival of nearly 90%. Due to the limited and poor-quality evidence, there is no global consensus on optimal management. Therefore, we performed a systematic review of the literature through the main electronic databases to deepen the current knowledge of this rare disease and discuss the available treatment strategies. Wide surgical excision is recommended as the standard-of-care treatment and should be tailored to the tumor position/extension and the patient’s performance status. The goal is to completely remove the tumor and achieve clear margins, thus reducing the rate of local recurrences. Non-surgical treatments, such as radiotherapy, chemotherapy, and topical approaches, can be considered, especially in the case of unresectable and recurrent disease. In the absence of clear recommendations, the decision-making process should be individualized, also considering the new emerging molecular targets, such as HER2 and PD-L1, which might pave the way for future targeted therapies. The current review aims to raise awareness of this rare disease and encourage international collaboration to collect larger-scale, high-quality evidence and standardize treatment.

1. Introduction

Vulvar Paget’s disease (VPD) is the most common extramammary Paget’s disease (EMPD) and accounts for approximately 1–2% of all vulvar neoplasms [1]. EMPD is an extremely uncommon skin malignancy, arising in apocrine gland-rich areas other than the mammary glands and accounting for 6.5% of all Paget’s diseases [2]. It originates from apocrine gland cells and then extends and proliferates within the epithelium [3]. The most common site of origin is the vulva (60–80%), followed by perineal areas (15%) and male genitalia (14%) [4]. Although it is generally limited to the epithelium, in approximately 10% of cases it may progress to invasive disease, metastasizing to local lymph nodes and distant organs [5]. According to Wilkinson and Brown’s classification, EMPD can be distinguished in two different subtypes: (1) primary (cutaneous origin), which originates in the epidermis and can be further classified as (i) in situ or intraepithelial (usual type), (ii) invasive, and (iii) associated with an underlying adenocarcinoma of a skin appendage; (2) secondary (non-cutaneous origin), which is the metastatic spread to the epidermis from (i) anorectal, (ii) urothelial, or (iii) other adenocarcinomas [6].
VPD mainly affects post-menopausal women over the age of 60 years. The clinical presentation is similar to mammary Paget’s disease and typically consists of erythematous or eczema-like chronic skin lesions associated with itchiness, tenderness, burning sensation, and occasionally pain [7]. Lesions are typically multifocal, mostly occur in the labia majora, and appear as well-demarcated patchy erythematous plaques, exhibiting the classic “strawberry and cream” pattern [8]. Given the rarity and non-specific clinical presentation, VPD is often misdiagnosed with dermatitis or eczema, and the correct diagnosis is frequently achieved when the disease is locally advanced [9]. However, with a 5-year overall survival of 75–90% and its indolent behavior, VPD has a favorable prognosis [10]. The initial diagnostic work-up should include a physical examination, staging imaging (pelvic ultrasound, magnetic resonance imaging, and/or computed tomography), and a vulvar excisional biopsy. Additionally, breast examination, coloscopy, cystoscopy, and serum tumor markers may be useful for the differential diagnosis between primary and secondary VPD [11].
Surgery is the mainstay of treatment, both in the primary and recurrent setting [12]. Despite its effectiveness, local recurrences are common, especially in the case of positive surgical margins—even if only pre-invasive disease is present—and multifocal microscopic disease [13]. Several conservative treatments have been described as an alternative to surgery in selected patients and their role needs to be clarified [14].
Currently, there is no global consensus regarding the optimal management of VPD, and thus, this review aims to summarize and critically evaluate the state-of-the-art knowledge of this rare disease providing insights that might be relevant for future treatment strategies.

2. Materials and Methods

2.1. Search Strategy

A comprehensive literature search was performed up to January 2023 across the following electronic databases: PubMed, EMBASE, Web of Science, Scopus and Cochrane library. The process of evidence acquisition combined the following key words and MESH terms: “vulvar Paget” and “vulvar Paget’s”. Search filters were applied to select clinically relevant articles from databases. The systematic review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol has not been registered.

2.2. Study Selection

In this systematic review, we included the following: (1) full-text English-language articles published in peer-reviewed journals starting from 1995; (2) original articles, including case reports; (3) primary histologically confirmed VPD; (4) description of treatment details and outcomes.
We considered as exclusion criteria the following: (1) primary vulvar tumors other than VPD; (2) secondary VPD; (3) cases with an uncertain diagnosis; (4) synchronous tumors; (5) studies focusing exclusively on histopathological, immunohistochemical, and molecular aspects; (6) studies with different aims than the analysis of treatment and outcome measures; (7) reviews, systematic reviews, meta-analyses, guidelines, books, editorials, letters, comments, conference abstracts, and preliminary studies with animal models.

2.3. Data Extraction and Analysis

Three authors (A.B., R.M., A.P.) independently screened article titles, abstracts, and full texts to ensure that all relevant studies were included. Cross-referenced studies identified from searched articles were also evaluated to integrate the literature search. Two authors (G.C. and R.G.) verified the inclusion criteria and excluded irrelevant studies and duplicate records. In the case of overlapping studies, we selected the most recent and/or most comprehensive manuscript. Two authors (I.P. and G.C.) carried out data extraction and quality assessment from all the retrieved studies based on full-text articles. Discrepancies between the investigators were resolved through a consensus. After careful selection of articles suitable for the review, we obtained the following information from each report: authors, year of study publication, study design and setting, number of patients, age, clinical history/presentation, histological and immunohistochemical features, tumor stage, molecular profile, type of treatment, adverse events, follow-up, disease control rate (DCR), recurrence rate, site of recurrence, progression-free survival (PFS), and overall survival (OS). Data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [15].

2.4. Statistical Analysis

Before data analysis, we performed an exploration phase of the data. The categorical data were described by frequency and percentage, with continuous data by mean, median, and range. If necessary, for the description of the endpoints, the percentages related to the number of patients or studies for which those specific data were available were reported. All analyses were performed using SPSS statistical software, version 20.0 (SPSS Statistics; International Business Machines Corporation [IBM], Armonk, NY, USA) for Mac.

3. Results

3.1. Study Selection

Figure 1 shows the flowchart of the systematic literature search process. The study selection resulted in a total of 281 relevant articles. Another 16 articles were identified via cross-referencing and hand-searching bibliographies. Through a process of screening, 96 studies met the inclusion/exclusion criteria, all with non-overlapping patients.

3.2. Study and Population Characteristics

The main characteristics of the included studies are detailed in Table 1. Of the 96 studies included, 5 were prospective, 24 were retrospective, 30 were case series, and 37 were case reports. No randomized controlled studies were found. The 96 selected studies involved a total of 5617 VPD patients, and among all studies, the sample size ranged from one patient in case reports to 2602 patients in larger series. The age at diagnosis across all studies ranged between 29 and 100 years (mean: 71 years). In 63–100% of the cases, the main sign at diagnosis was an erythematous/eczematoid lesion of the vulva, and persistent vulvar itching was the most commonly reported symptom (8–100%). The less common symptoms/signs were vulvar burning (7.2–70.8%), vulvar pain (5.9–45.8%), vaginal discharge (4–13.9%), and bleeding (2–16.3%). Approximately 7–30% of reported cases were micro-invasive, while 5–67.8% were invasive.

3.3. Treatment Approches

Surgery was the first treatment choice in most studies (75%). The main surgical approach consisted in a wide local excision (10–96.7%), followed by partial simple vulvectomy (2.9–88%), radical vulvectomy (4.2–58%), total simple vulvectomy (2–62.5%), hemivulvectomy (9.7–28%), and skinning vulvectomy (1–37.5%). According to the reports, the margin status was positive in the range of 7.1% and 91.7%. In the case of positive margins and/or positive lymph nodes, patients underwent external beam radiotherapy (RT) with a total dose ranging between 23 Gy and 61 Gy. For unresectable disease, radical external beam RT was used up to a total dose of 63 Gy. Among RT approaches, Boron Neutron Capture Therapy (BNCT) was delivered in a radical setting. Systemic chemotherapy was almost exclusively used in the case of metastatic disease with palliative intent and very rarely in the neoadjuvant and adjuvant settings. The most commonly reported antineoplastic agents included bleomycin, mitomycin, 5-fluorouracil, cisplatin or carboplatin, paclitaxel or docetaxel, and trastuzumab. Local approaches included topical chemotherapy with imiquimod 5%, laser therapy, and photodynamic therapy using methyl 5-aminolevulinic acid or hematoporphyrin derivatives as a photosensitizer. Details on the treatment strategies are described in Table 2.

3.4. Outcomes

When reported, the outcome measures varied widely across the included studies. The pooled median follow-up ranged between one month and 9 years. The disease control rate was achieved in 50–100% of patients. The recurrence rate ranged between 23% and 73%, with a mean time to recurrence of 1–4.4 years. The progression-free survival rates ranged between 0.5 and 5 years, and the overall-free survival ranged between one and 8 years. No significant postoperative complications or treatment-related toxicities higher than grade 3 were reported. Where available, data on the type of treatment at recurrences are outlined in Table 3. In cases of local recurrence, surgical excision remained the most frequent treatment choice, followed by topical approaches (using imiquimod and 5-fluorouracil) and RT. Systemic chemotherapy was mainly used in the case of distant progressive disease. Given the high heterogeneity, it is difficult to provide an exhaustive summary and draw definitive conclusions. Details on the outcomes of each study are shown in Table 3.

4. Discussion

Due to the rarity and absence of standardized guidelines, the management of VPD poses a huge challenge in clinical practice [9,14,111]. In the present systematic review, we collected the best available evidence on this rare disease and analyzed the clinical decision-making process, treatment, and outcomes of 5617 VPD patients from 96 different studies. Given the high heterogeneity of the studies and population characteristics, a meta-analysis was not feasible.
This review confirmed that VPD patients are mostly postmenopausal women with a mean age of approximately 70 years, presenting with an itching, persistent erythematous lesion of the vulva. The final diagnosis of VPD was achieved late in most of the cases that were treated in non-referral centers. The diagnostic pathway and treatment strategies varied widely across the analyzed studies. Surgery was the first choice for the primary treatment of VPD with a recurrence rate of 20–70%. Depending on the site and extent of the lesion, the surgical approaches ranged from wide local excision to radical vulvectomy with a reconstruction flap. To date, there is no consensus on which surgical technique minimizes local recurrence. There is, therefore, the need to better define novel surgical prognostic factors and promote global standardization to minimize long-term morbidity and improve patient care and quality of life [112]. Preoperative vulvovaginal intensive biopsy mapping (called “clock mapping”), both inside and outside visible lesions, became a useful workup tool for predicting the invasiveness and extension of VPD and tailoring the radicality of surgery [113]. Inguinofemoral lymphadenectomy (or sentinel lymph node biopsy) should be performed in invasive diseases. Re-excision can be considered in cases of positive resection margins. Due to the multifocality and irregular shape of VPD lesions, the surgical margins are often positive and local relapses are frequent. Surgery was the preferred option to treat local recurrences, even if adjuvant RT could be delivered in the case of positive margins, dermal invasion, or lymph node metastasis.
The role of non-surgical therapies, such as RT, topical imiquimod, chemotherapy, photodynamic therapy, and laser CO2 therapy, remains unclear and can be considered in cases of unresectable, recurrent, and metastatic disease, as well as a valid conservative alternative for non-invasive disease [5,114,115]. It is noteworthy that preliminary results indicated that noninvasive physical plasma might be a viable treatment option for women with a cervical intraepithelial neoplasia, and this approach might be explored for VPD patients as well [116]. The role of RT as an option in the treatment of VPD has not been fully understood. As RT appeared unsatisfactory in the adjuvant setting, further investigation into the potential role of combining RT with immunotherapy is warranted. The role of radical RT in elderly patients with surgical contraindications or as an alternative to surgery in the recurrent setting remains unclear. However, it should be stressed that, across the selected studies, the technical details on RT were rarely reported and, where available, the protocols varied widely across the reports, underlining the need to standardize the doses and volumes in future multicenter studies. Moreover, there were no reports on particle beam RT in this challenging scenario, and considering the ballistic and radiobiological advantages of this innovative technique, this approach should be tested in the future to reduce toxicities and improve the total dose to the target. Moreover, even if systemic therapy should be recommended for metastatic VPD patients, further research is needed on the role of chemotherapy in the neoadjuvant and adjuvant settings.
Overall, the prognosis of VPD patients is favorable. Natural history shows high rates (50–100%) of disease control at primary diagnosis. However, the rate of local recurrences is also high, and repeated surgical procedures can be mutilating and impair quality of life. Therefore, in the era of precision medicine, novel targeted therapies are urgently needed. Owing to the rarity and lack of high-level evidence on VPD, standardized follow-up protocols are also lacking. The follow-up should consider regular vulvar inspection, vulvoscopy, re-biopsy in suspicious cases, and CT/MRI in cases of distant lesions.
There were lacking data on the potential identification of molecular targets. The strong heterogeneity found in the histopathological and immunophenotypic reports highlights the importance of promoting centralized histological reviews of these rare specimens to ensure a correct diagnosis and standardize the management and patient care. Indeed, determining the expression of hormone receptors, as well as the human epidermal growth factor receptor 2 (HER2) or the programmed death-ligand 1 (PD-L1) status, is crucial to paving the way for personalized targeted therapy, especially in cases of advanced/metastatic disease or recurrence [117]. In a recent systematic review and meta-analysis including patients with extramammary Paget’s disease, the expression rates of hormones receptors were 12% (95% CI = 0.03–0.36) for estrogen receptors (ERs), 9% (95% CI = 0.03–0.25) for progesterone receptors (PRs), and 40% (95% CI = 0.34–0.47) for androgen receptors (ARs) [118]. This appears in contrast with results of Garganese et al. who reported the following expression rates: 70% ER, 20% PR, and 75% AR positivities among 41 patients with VPD [119]. Of note, no significant differences in terms of hormone expression were seen between invasive and non-invasive diseases. Anti-hormonal targeted therapy represents an interesting treatment option worth further investigation. HER2 overexpression was found in 32% of women with extramammary Paget’s disease [118], and its status needs to be assessed due to its pathogenetic role and correlation with nodal metastases, local invasion, and recurrence rates. However, more data regarding the HER2 status in VPD are required before drawing definitive conclusions about the potential use of biological therapies targeting HER2. Moreover, still, too little is known about the PD-L1 and tumor-infiltrating lymphocyte (TIL) status in vulvar Paget’s disease. Data on PD-L1 expression were first reported by Garganese et al. based on a cohort of 41 patients (10% non-invasive VPD and 27% invasive VPD) and are interesting as they might open up the possibility of using immunotherapy, either alone or in combination with RT [119,120].
The major limitations of this review are the small sample sizes and the long study periods (from 1995 to 2022), which could reflect several changes in the histological diagnosis and treatment management (surgical and RT technologies, as well as available chemotherapy schedules). Therefore, no definitive conclusions on the impact of these treatments on outcomes can be drawn. Moreover, the heterogeneity of the analyzed population, missing data, the study design (mainly case reports or case series), and the absence of controlled arms represent other relevant limitations. On the other hand, phase III randomized studies are not feasible and an evidence-based approach for these rare tumors is not so easy. Oncological prospective registers and enrollment in basket clinical trials, including VPD, are warranted, especially in the advanced/metastatic and recurrent setting. Despite the heterogeneity, our data contribute to the limited literature evidence by drawing more attention to VPD patients and highlighting the need of optimizing the clinical decision-making process and standard of care.

5. Conclusions

In the present systematic review, we summarized the state-of-the-art literature evidence on the vulvar Paget’s disease, with a focus on available treatment approaches and outcomes. Due to the rarity of the disease, the low-quality evidence (mostly small retrospective studies), and the huge heterogeneity in terms of reported treatment strategies and outcome measures, it is not possible to obtain clear recommendations on the best management. Our findings emphasize that VPD patients should be centralized in referral centers and managed through high-skilled collaborative networks, with a multidisciplinary approach where the treatment strategy is discussed on a case-by-case basis. The centralization of care for rare tumors has already proved to significantly increase patient outcomes. Strong inter- and multidisciplinary collaborations are crucial to create networks, sharing data and comparing different single-institution experiences. International databases are urgently needed as they may lead to a real step forward in understanding such a challenging disease.

Author Contributions

Conceptualization, G.C. and I.P.; methodology, A.B., R.M. and R.G.; resources, A.P., R.M. and R.G.; data curation, A.P., R.M., R.G., M.G.V. and A.P.; writing—original draft preparation, A.B., R.M. and R.G.; writing—review and editing, G.C.; visualization, G.C. and I.P.; supervision, I.P.; project administration, G.M., S.P. and I.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

We would like to thank the MITO Rare Cancer Group for its support. G.C. is a fellow of the PhD in “Network Oncology and Precision Medicine”, Department of Experimental Medicine, Sapienza University of Rome.

Conflicts of Interest

The authors declare no conflict of interest.

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Cancers 15 01803 g001 550
Figure 1. Flowchart of the systematic literature search process. The study selection resulted in a total of 281 relevant articles.
Figure 1. Flowchart of the systematic literature search process. The study selection resulted in a total of 281 relevant articles.
Cancers 15 01803 g001
Table
Table 1. Main characteristics of the included studies.
Table 1. Main characteristics of the included studies.
ReferenceType of StudySample Size, nMean Age (Years, Range)Symptoms (%)Signs (%)Tumor Invasion
Kodama et al. 1995 [16]Cs3067.6 (41–82)Vulvar itching (100%)Erythema (63%)10 ni-VPD (33.3%); 9 mi-VPD (30%); 11 i-VPD (36.7%)
Fishman et al. 1995 [17]Cs1470.5 (57–83)Vulvar itching (100%)NRNR
Yoshitatsu et al. 1997 [18]Cr168Vulvar itchingVulvar erythema with a nodule on the left labium majorni-VPD
Goldblum et al. 1997 [19]Cs1965 (56–86)NRNR5 i-VPD (26.3%)
Fanning et al. 1999 [20]Ra10070 (35–100)Vulvar itching (NR)NR7 mi-VPD (7%); 5 i-VPD (5%)
Henta et al. 1999 [21]Cr174PainIrregular border dark red massni-VPD
Murata et al. 1999 [22]Cs1 (extracted from a total of 6 pts)78NRErythemai-VPD
Louis-Sylvestre et al. 2001 [23]Ra5267.4 (39.6–94.7)NRNRNR
Wilkinson et al. 2002 [6]Cs376 (76–81)Vulvar inflammatory lesion (66%); urinary urgency (33%)Erythematous and eczematoid lesion (66%); periurethral induration and scar tissue surrounding the urethral meatus (33%)NR
Tebes et al. 2002 [24]Cs2369(46–84)Itching (78%), burning sensation (52%), dysuria (4%), watery discharge (4%)Vulvar lesion (87%)6 i-VPD (26.1%)
Luk et al. 2003 [25]Cs1 (extracted from a total of 6 pts)55NRNRNR
Wang et al. 2003 [26]Cr175Itching and burningHypopigmented to pink plaque in labium majorNR
Chin et al. 2004 [27]Cr165NRNRNR
Zawislak et al. 2004 [28]Cr1668 years of persistent vulvar itchingPurple-red, well-demarcated, moist lesion on the left labia majoraNR
Bhattacharya et al. 2005 [29]Cr159vulvar irritationNRni-VPD
Raspagliesi et al. 2006 [30]Prospective pilot study763 (50–75)Severe vulvar itching (NR)NRNR
Yanagi et al. 2007 [31]Cr284 (82–86)NRInfiltrated reddish plaque on the genital regionNR
Hatch et al. 2008 [32]Cs264 (60–68)Pain (100%), urinary retention (50%)Vulvar erythemaNR
Karam et al. 2008 [33]Cr134NRNRNR
Challenor et al. 2009 [34]Cs257 (48–66)Itching (100%), soreness (50%)Vulvar erythemaNR
Sendagorta et al. 2010 [35]Cs366 (58–82)Itching (66.6%), burning (33.3%)Vulvar lichenified plaque (33.3%), vulvar erythematous plaque (66.6%), vulvar erosions (1–33.3%)NR
Shaco-Levy et al. 2010 [36]Cs5669 (42–89)Vulvar itching (91%),
vulvar pain (11%), drainage (5%), bleeding (2%)		Erythematous-white plaque (98%)0.2–6 mm
Roh et al. 2010 [37]Cs1166.6PruritisNRNR
Anton et al. 2011 [38]Cr184ItchingHyper-pigmented to the pink plaque from the pubic area to the left great labiaNR
Feldmeyer et al. 2011 [39]Cr159Fluctuating soreness and itchingPoorly delimited erythematous–squamous patch on the right labia majorNR
Hanawa et al. 2011 [40]Cr170AsymptomaticIncreasing vulvar erythema, slightly raised erythematous lesion with ulcers, hemorrhagic granulomatous lesionNR
Jones et al. 2011 [41]Ra5067.6Itching (54%)NRNR
Tonguc et al. 2011 [42]Cr165ItchingHyperkeratotic erythematous lesion from right labium to the clitorisNR
Mendivil et al. 2012 [43]Cs1675 (53–84)Pruritis (100%)NR3 i-VPD
Al Yousef et al. 2012 [44]Cr178PruritisErythemaNR
Baiocchi et al. 2012 [45]Cs462.2 (56–80)Itching (100%)Vulvar erythematous plaque (100%), vulvar erosions (100%)NR
Wakabayashi et al. 2012 [46]Cr168NRNRNR
Cai et al.
2013 [47]		Ra4368.6 (52–85)Itching (95.3%), vulvar pain (18.6%), bleeding (16.3%), and discharge (13.9%)Erythematous lesions (81.4%), ulceration (32.6%), erosion (30.2%)NR
Choi et al. 2013 [48]Cs3 (extracted from a total of 10 pts)73 (65–81)NRVulvar erythemaNR
Gavriilidis et al. 2013 [49]Cr175Rash and vulvar itchingEczematoid and erythematous area of the genitaliaNR
Sanderson et al. 2013 [50]Cs671.5 (58–85)Soreness (50%), itching (50%), irritation (16,6%), inflammation (16.6%) pain (16.6%)PlaqueNR
De Magnis et al. 2013 [51]Ra3468.7Itching (76.5%), burning (58.8%)NRi-VPD: 11.7%
Treglia et al. 2013 [52]Cr161NRNRNR
Magnano et al. 2013 [53]Cr184Slight pruritusErythematous ulcerated and well-demarcated oval plaque (5 × 3 cm)ni-VPD
Marchitelli et al. 2014 [54]Cs1071.9 (60–92)NRErythematous plaqueNR
Liu et al. 2014 [55]Ra8564.4 (33–82)Pruritis (74.1%), pain (5.9%)NRi-VPD: 20%
Luyten et al. 2014 [56]Ra2066.4 (41–84)NRNRNR
Carrozzo et al. 2014 [57]Cs4 (based on a total of 5 pts)69 (59–79)NR
  • Case 1: itchy erythematous lesion
  • Case 2: itchy dermatosis in the vulvar region+ erythematous–eczematoid lesion in the inferior perivulvar region
  • Case 3: itchy dermatosis in the perivulvar region
  • Case 4: itchy dermatosis in the perivulvar region
NR
Frances et al. 2014 [58]Cr180NRItching eczematous plaquesni-VPD
Hata et al., et a. 2015 [59]Ra2169 (53–88)NRNRNR
Asaka et al. 2015 [60]Cr180Vulvar itching, painPigmented vulvar, perianal erythematous plague, and a subcutaneous nodule in the left major labiaIntradermal invasion
Sopracordevole et al. 2016 [61]Ra2766.5 (36–88)Itching (64.3%), burning + itching (14.3%), pain (14.3%), burning (7.2%)Erythema (93.7%), hyperkeratosis (31.6%)8 mi-VPD (29.6%)
3 i-VPD (11.1%)
Cowan et al. 2016 [62]Prospective pilot study871.5 (47–78)Itching (63%), burning (25%), pain (25%)Visible lesions (100%), erythema (75%), anal involvement (13%)NR
Fan et al. 2016 [63]Ra1865Pruritus, erosions, burning sensation, painErythematous patches (50%), hypopigmentation (50%), hyperpigmentation (27.8%)NR
Nagai et al. 2016 [64]Cs275 (69–81)ItchingEczemaNR
Onaiwu et al. 2016 [65]Ra8967(32–89)Pruritus (48.3%)NR7 i-VPD (7.9%)
Hillmann et al. 2016 [66]Cr148ItchingAcetowhite areas in left minora and majora labia, perineal, and anterior perianal regionsNR
Liau et al. 2016 [67]Ra374.7 (66–83)Pruritus, painErythematous patch or plaqueNR
Jeon et al. 2016 [68]Cr171Pruritus, painErythematous plaque on both labia majorani-VPD
Dogan et al. 2017 [69]Cr173ItchingLeft vulvar erythemaIntradermal pagetoid cells
Vicentini et al. 2017 [70]Cr162Itching, pain, discomfortErythematous plaqueni-VPD
Parashurama et al. 2017 [71]Cs1876.9Vulvar itching, sorenessUlcer, mass, pigmented lesionNR
Konstantinova et al. 2017 [72]Cs18165NRNRNR
Mota et al. 2017 [73]Cr178PruritusCutaneous plaque with eczemaNR
Long et al. 2017 [74]Cs9070.3NRNRNR
Kato et al. 2018 [75]Cr272.5 (64–81)Nodules and skin infiltrationsBoth inguinal lymph nodesni-VPD
Borghi et al. 2018 [76]Ra7967.5 (53–77)NRNRmi-VPD/i-VPD: 12.7%
Sawada et al. 2018 [77]Ra982 (61–94)NRNRni-VPD
Hiratsuka et al. 2018 [78]Cs1 (extracted from a total of 4 pts)69NRNRi-VPD
Hsieh et al. 2018 [79]Cr154NRNRNR
Nitecki et al. 2018 [80]Cs4467Pain (10–22%), pruritis (10–22%), pain + pruritis (6–13%)NRi-VPD: 20%
Rioli et al. 2018 [81]Ra1370 (52–84)NRNR3%
Kato et al. 2018 [82]Ra17 (7 women)76.9NRNRi-VPD
Cai et al. 2018 [83]Cs864.4NRNRNR
Bouceiro-Mendes et al. 2019 [84]Cr172Vulvar itchingErythematous plaqueNR
Loiacono et al. 2019 [85]Cs2469.3 (38–84)Itching + burning + pruritus + vulvar lesions (21%), pain + pruritus (13%), vulvar itching (4%), pruritus (4%), unknown (58%)NRNR
Mujukian et al. 2019 [86]Cr184NRLarge erythematous plaque affecting the right labia majoraNR
Molina et al. 2019 [87]Cs350 (50–70)Fatigue, weakness, pruritus, feverErythematous plaque, scattered, pink-red plaquesNR
Hirai et al. 2019 [88]Cs565 (53–74)NRNRNR
van der Linden et al. 2019 [89]Ra11373 (41–97)NRNRni-VPD: 77%
mi-VPD: 8.8%
i-VPD: 14.2%
Panoskaltsis et al. 2019 [90]Cr175Itching, irritation, and burningErythematous plaque with white scalingi-VPD
Nasioudis et al. 2020 [91]Ra260272 (31–90)NRNRi-VPD: 61.8%
Bartoletti et al. 2020 [92]Cs462.5 (45–74)Vulvar itchingNRNR
Bruce et al. 2020 [93]Cr137Vulvar irritation at 7 weeks gestation with an erythematous, edematous left labiaNRNR
Noel et al. 2020 [94]Cr165Vulvar itchingVulvar reddish lesionNR
Kilts et al. 2020 [95]Ra126873 (29–100)NRNRNR
Rathore et al. 2020 [96]Cr159Vulvar itchingVulvar redness, erythematous indurated plaque with multiple papules and nodulesNR
Sarkar et al. 2020 [97]Cr151Vulvar itching for 3 yearsErythematous patchy lesionNR
Sopracordevole et al. 2020 [98]Ra1065.5 (40–80)Vulvar itchingRed asymmetrical areas, ulcerations, hyperkeratotic red areas, whitish areasmi-VPD
Stasenko et al. 2020 [99]Ra2662 (29–77)NRNRmi-VPD
Liang et al. 2021 [100]Cs3864.4 (39–79)Vulvar itching and painNRNR
Hirata et al. 2021 [101]Cr155Recurrent fever for 10 months, inguinal and intraperitoneal lymphadenopathiesNRNR
Kosmidis et al. 2021 [102]Cr275 (69–81)Vulvar itching and burning sensation; perineal and vulvar itching and swellingErythematous plaque
Eczematous plaque + erosion		ni-VPD
Mazzilli et al. 2021 [103]Cr160NRNRNR
Preti et al. 2021 [104]Ra12265 (36–92)Itching (59–61%), burning sensation (18%), itching + burning (20–21%)NRmi-VPD: 21%
i-VPD: 16.8%
Liu et al. 2021 [105]Ra5472 ± 7 (SD)NRNRNR
Ferrara et al. 2021 [106]Prospective study1079 (67–92)NRNRNR
Bajracharya et al. 2022 [107]Cr170Vulvar itching and a gradually progressive reddish lesionNRNR
Wang et al. 2022 [108]Prospective pilot study2 (extracted from a total of 11 pts)73 (67–79)NRNRNR
Borella et al. 2022 [109]Ra5563 (36–92)Itching (29–59%), burning (15–27%)NRNR
Van der Linden et al. 2022 [110]Prospective study2467 (42–84)Itching (83%), pain (45.8%), burning sensation (70.8%), strangury (29.2%), dyspareunia (38.5%)Erythema (100%), scaling (62.5%), ulceration (25%)NR
AWD = alive with disease; Cr = case report; CR = complete response; Cs = case series; CT = chemotherapy; DCR = disease control rate; DID = died of intercurrent disease; DOD = died of disease; HV = hemivulvectomy; i-VPD = invasive vulvar Paget’s disease; LA = lymphadenectomy; LFU = lost to follow-up; LN = lymph node; MAL-PDT = methyl 5-aminolevulinic photodynamic therapy; mi-VPD = microinvasive vulvar Paget’s disease; NED = no evidence of disease; ni-VPD = noninvasive vulvar Paget’s disease; NR = not reported; PD = Progressive disease; PR = partial response; pts = patients; PV = simple partial vulvectomy; R = residual disease; Ra = retrospective analysis; RT = radiotherapy; RV = radical vulvectomy; SD, standard deviation; SV = simple vulvectomy; TZB = trastuzumab; Vu = vulvectomy; w = weekly; WLE = wide local excision.
Table
Table 2. Overview of treatment approaches.
Table 2. Overview of treatment approaches.
ReferenceSurgeryRadiotherapySystemic ChemotherapyOther Therapy
NTechnique Margin StatusComplicationsNAim Total Dose/Fr Technique VolumesToxicityNAim SchemeToxicityN
Kodama et al. 1995 [16]29ni-VPD: RV + bilateral LA + skin graft (30%), RV + bilateral LA (20%), SV (30%), SV + skin graft (10%), RV + bilateral LA + skin graft + perineal resection and artificial anus (10%)
Margin status: R+ in 4 cases (40%)

mi-VPD: RV + bilateral LA + skin graft (44.4%), SV (33.3%), RV + bilateral LA (22.2%)
Margin status: R+ in 5 cases (55.6%)

i-VPD: RV + bilateral LA + skin graft (27.3%), RV + bilateral LA (27.3%), RV + bilateral LA + skin graft + total hysterectomy (9%), exploratory laparotomy (9%), resection (9%), RV + bilateral LA + skin graft + perineal resection and artificial anus (9%)
Margin status: R+ in 4 cases (36.4%)		NR3NRNR11Aim: palliative
Scheme: bleomycin, mitomycin, FCAP (5-FU, cyclophosphamide doxorubicin, cisplatinum)		NRNR
Fishman et al. 1995 [17]14Primary surgery: WLE (57.1%), SV (21.4%), RV (21.4%)

Recurrent surgery: WLE (78.6%), SV (7.1%), WLE + bilateral LA + rectus abdominal myocutaneous reconstruction (7.1%)

Margin status: R+ in 5 cases (35.7%)		NR1Aim: adjuvant
Total dose/Fr: NR
Volumes: vulvar, pelvic and groin RT		NR0--0
Yoshitatsu et al. 1997 [18]1Lesion resection + LA + gracilis musculocutaneous flap → WLE + split-thickness skin graft

Margin status: NR		NR0--1Aim: adjuvant
Scheme: mitomycin C and Tegafur		NR0
Goldblum et al. 1997 [19]19ni-VPD: SV (10), RV (2), RV + LA (1)
Margin status: NR

i-VPD: RV (3), SV (2), RV + LA (1)
Margin status: R+		NR0--0--0
Fanning et al. 1999 [20]100WLE (32%)
RV (58%)
HV (10%)

Margin status: NR		NR0--0--0
Henta et al. 1999 [21]0--1Aim: palliative, electron beam irradiation
Total dose/Fr: 5000 cGy
Volumes: vulvar lesion		NR1Aim: palliative
Scheme: etoposide (VP16) 100 mg for 5 days concomitant with RT		NR1 (photodynamic therapy with aminolevulinic acid)
Murata et al. 1999 [22]0--1NRNR0--0
Louis-Sylvestre et al. 2001 [23]31WLE (67.7%)
Vu (22.6%)
HV (9.7%)

Margin status: R+ in 6 cases of Vu		NR0--0--21
Wilkinson et al. 2002 [6]3Case 1: RV
Case 2: RV, with excision to the fascia and partial vaginal excision, including excision of the hymen
Case 3: 2 subsequent partial Vus ➝ periurethral
scar tissue excision

Margin status:
Case 1: R0
Case 2: R0
Case 3: NR		NR0--0--0
Tebes et al. 2002 [24]23WLE o PV (73.9%)
Radical resection + LA (26.1%)

Margin status: R+ in 13 cases (50%)		NR0--0--0
Luk et al. 2003 [25]1RV + LA

Margin status: NR		NR1Aim: adjuvant
Total dose/Fr: 60 Gy⁄30 fr⁄6 weeks to primary site and right inguinal nodal site 32 Gy⁄8 fr⁄2 weeks at 90% isodose level for prophylactic left inguinal nodal RT
Volumes: anteroposterior opposed photon fields to pelvis and vulva, then electron boost to right vulva, matched 10 MeV electron fields to bilateral inguinal nodal sites		Confluent wet desquamation, resolved at 4 weeks post-RT, mild acute small bowel irritation0--0
Wang et al. 2003 [26]1WLE
Margin status: NR		NR0--0--1
Chin et al. 2004 [27]1SV → WLE + rectus abdominal flap
Margin status: NR		NR0--0--0
Zawislak et al. 2004 [28]0--0--0--1 (photodynamic therapy)
Bhattacharya et al. 2005 [29]1PV → 4 excisions → hysterectomy + salpingo-oophorectomy + LA + SV + partial vaginectomy

Margin status: NR		NR0--0--0
Raspagliesi et al.
2006 [30]		5Vu or WLE
Margin status: R+		NR0--0--2
Yanagi et al. 2007 [31]0--2Aim: radical
Total dose/Fr: electron beam of 4 MeV, 2.25 Gy per day, 4 days/week to a total dose of 45 Gy.
Volumes: a 10 mm margin surrounding the lesion

Aim: radical
Total dose/Fr: X-rays of 4 MV, 2.5 Gy per day, 4 days/week to a total dose of 45 Gy + electron beam therapy (4 MeV, 3.0 Gy per day, for 5 fractions to a total dose of 15 Gy)
Volumes: thick lesions on both sides of the genitals		mild acute mucositis (2)0--0
Hatch et al.
2008 [32]		2Local resection (1), RV (1)
Margin status: NR		NR0--0--2
Karam et al.
2008 [33]		1Surgical excisions of the vulva and perineum (8 times)

Margin status: NR		NR---1Aim: palliative
Scheme: 3-w-TZB (14 cycles)		None0
Challenor et al. 2009 [34]2Skinning Vu and reconstruction with split skin graft (1), skinning Vu with reconstruction via V-Y advancement flaps (1)
Margin status: R+		NR0--0--2
Sendagorta et al. 2010 [35]1Skinning posterior vulvectomy with reconstruction (1)NR0--0--3
Shaco-Levy et al.
2010 [36]		56Conservative procedures: WLE, SV, PV.

Radical procedures: complete Vus and RVs

Margin status: R1 in 44%		Skin flap/graft breakdown and necrosis (6); wound infection (2); hypertrophic scar (2); thigh cellulitis (1)6Aim: adjuvant

Details on RT available only for 1 case
Total dose/Fr: 2340 cGy to the groins, pelvis, and anus, with a 4500 cGy boost to
the groins and anus and 6100 cGy electron boost to the peri-anal region		NR0--0
Roh et al. 2010 [37]11WLE: 63.6%
RV: 18.1%
SV: 18.1%
Margin status: R+ in 72.7%		-0..0-0-
Anton et al. 2011 [38]0--0--0--1
Feldmeyer et al. 2011 [39]0--0--0--1
Hanawa et al.
2011 [40]		0---Aim: palliative
Total dose/Fr: NR
Technique: NR
Volumes: NR		NR-Aim: palliative
Scheme: w-TZB for 5 weeks ➝ w-paclitaxel plus w-TZB 6 cycles		NR0
Jones et al. 2011 [41]50WLE: 24%
HV: 28%
RV: 28%
Anterior vulvectomy: 14%
Skinning vulvectomy: 2%
SV: 2%

Margin status: R+ in 54%		-0--2NR-0
Tonguc et al. 2011 [42]1WLE → WLE
Margin status: R+ → R0		NR0--0--1
Mendivil et al. 2012 [43]16SV: 62.5%
RV: 12.5 %

Only biopsy: 12.5%
Margin status: R+ in 68.8%		NR0--0---
Al Yousef et al. 2012 [44]0--0--0--1
Baiocchi et al. 2012 [45]2SV (1), WLE (1)

Margin status: R+		NR1Aim: adjuvant
Total dose/Fr: 54 Gy
Technique: external RT
Volumes NR		NR 4
Wakabayashi et al.
2012 [46]		1WLE and radical hysterectomy ➝ resection of recurrence in the right pelvic floor

Margin status: NR		NR0--1Aim: palliative
Scheme: 3-w-TZB (17 cycles)		Moderate headache and flushing during the first infusion, no other adverse effects0
Cai et al.
2013 [47]		35(1) Radical surgery (RV +/− inguinal LA): EMPDV + adnexal adenocarcinoma (100%), intraepithelial EMPDV (44%), i-VPD (42.8%);
(2) Conservative surgery (WLE and SV): i-VPD (57.2%), intraepithelial EMPDV (56%)

Margin status:
R+: 45.8% in intraepithelial EMPDV, 42.8% in i-VPD and 66.7% in EMPDV + adnexal adenocarcinoma		NR17Median total dose/fr:
primary radical RT (8): median total dose 60 Gy/20 fr (60–63 Gy)/20–29 fr);
Adjuvant RT after surgery (6): median total dose 57 Gy (range = 39–60 Gy);
Preoperative RT (1): total dose 43.30 Gy;
Rescue RT (1): 63 Gy
Palliative RT in tibial metastasis (1): NR

Technique: Co60 or 9 MeV electrons

Volume: pelvic, para-aortic,
vulvar, inguinal, tibial		NR1Aim: neoadjuvant before surgery
Scheme: 2 cycles of unspecified CT		NR0
Choi et al. 2013 [48]3WLE
Margin status: NR		NR0--0--3 (topical imiquimod)
Gavriilidis et al.
2013 [49]		1RV with bilateral inguinal LN dissection

Margin status: R0		NR0--0--0
Sanderson et al. 2013 [50]2Vu (1), skinning posterior Vu with reconstruction (1)NR0--0--6 (topical imiquimod)
De Magnis et al.
2013 [51]		34WLE (61.7%)
Partial SV (29.4%)
RV (5.9%)
Total SV (2.9%)

Margin status: R+ in 44.1%		NR0--0--0
Treglia et al. 2013 [52]1Radical excision
Margin status: R-		NR0--0--0
Magnano et al. 2013 [53]0--0--0--Photodynamic therapy with aminolevulinic acid
Marchitelli et al.
2014 [54]		0--0--0--10
Liu et al.
2014 [55]		69WLE (17.4%), PV (2.9%), SV (37.6%), RV (34.7%)

Margin status: R+ in 34.5%		NR4NR-0--0
Luyten et al.
2014 [56]		0--0--0--20
Carrozzo et al. 2014 [57]0--4Radical HDR brachytherapy with 188Re (Dermo-Beta-Brachytherapy, DBBT)
-
first course (4 pts; 50 Gy for 300 µ)
-
second course (3 pts; 50 Gy for 300 µ)
Burning sensation and superficial erosions, followed by small crusts, which resolved in 2–3 weeks after DBBT session0--0
Frances et al. 2014 [58]0--0--0--Topical imiquimod 5%
Hata et al., et a. 2015 [59]21Surgical excision (no other details)
Margin status: R+ in 16 cases (76.2%)		NR16Aim: adjuvant
Volume 1: tumor bed Median total dose: 59.4 Gy (range, 45–648 Gy) in 30 fractions (range, 23–36 fractions)

Volume 2: pelvic and inguinal lymph node area; total dose: 44–50. 4 Gy. In 3 cases (who had not undergone lymph node removal): total doses of 56, 60 and 612 Gy were delivered with the shrunken field to the enlarged inguinal lymph nodes of the three patients		Acute: 8 cases grade 1 leukopenia;16/16 ≤ grade 2 dermatitis, 9 grade 1 colitis
3 grade 1 cystitis
no grade ≥ 3.
Late telangiectasia grade 1		0--0
Asaka et al. 2015 [60]1Excisional procedures
Wide local excision

Margin status: NR		NR0--0---
Sopracordevole et al. 2016 [61]25WLE (5–20%)
Partial SV (8–32%)
Total SV (9–36%)
Skinning (1–4%)
Total vulvectomy (2–8%)
Total vulvectomy with inguinofemoral lymphadenectomy (11–40.7%)

Margin status: R0		NR0--0--2: CO2 laser excision
Cowan et al.
2016 [62]		8Unilateral PV (5), bilateral PV (1), multiple vulvectomies and skin flaps (1)

Margin status: R1 microscopic		NR0--0--0
Fan et al. 2016 [63]1810 local excision (55.5%)
3 WLE (16.7%)
5 SV (27.8%)

Margin status: R1 in 3 cases (16.7%)		NR0--0--0
Nagai et al. 2016 [64]2Wide local excision + split-thickness skin graftGraft infection0--0--0
Onaiwu et al.
2016 [65]		74WLE (61.8%)
RV (14.6%)
Skinning vulvectomy (4.5%)
Mohs surgery (2.3%)

Margin status: R1 in 47 cases (63.5%)		NR0--0--15
Hillmann et al. 2016 [66]1Radical vulvectomy and bilateral inguinal lymphadenectomy

Margin status: R0		NR0--0--0
Liau et al. 2016 [67]21 WLE
1 Laser vulvectomy

Margin status: NR		NR0--0--3: topical imiquimod 5% cream
Jeon et al. 2016 [68]1Minimal excision with a 1 cm safety margin
Margin status: R0		NR11.8 Gy per day, 5 times per week, up to 50.4 Gy over 6 weeks to perineum, both inguinal lymph nodes, followed by 19.8 Gy to perineum for 2 weeksMinimal excision with a 1-cm safety margin0--0
Dogan et al. 2017 [69]1HV → WLE
Margin status: R+ → R+		NR0--0--1 (topical imiquimod)
Vicentini et al. 2017 [70]0--0--0--1 (topical imiquimod, laser, photodynamic therapy
Parashurama et al. 2017 [71]18WLE (88.9%)
Radical excision (11.1%)
Margin status: R1 in 13 cases (72.2%)		NR345 Gy in 25 fractions was delivered to the pelvis over 5 weeks with a boost to the vulva of 9 Gy in 5 fractionsNR0--0
Konstantinova et al. 2017 [72]102WLE, local resections, or vulvectomies
Margin status: NR		NR0--0--0
Mota et al. 2017 [73]1SV
Margin status: NR		NR0--0--0
Long et al. 2017 [74]90WLE (96.7%)
Abdominoperineal resection (3.3%)
Margin status: R1 in 39.2%		NR0--0--0
Kato et al. 2018 [75]21: wide local excision of the primary site and biopsies of both inguinal lymph nodes
1: wide local excision and left groin lymph node dissection		NR2Aim: adjuvant at ilioinguinal areas and iliac regionNR2Aim: palliative
Scheme:
1° line CT: docetaxel (60 mg/m2)
2° line CT: TS-1 (100 mg/body)
NR0
Borghi et al. 2018 [76]79Vulvar resection, simple vulvectomy, radical vulvectomy. Locoregional (inguinal or pelvic) lymphadenectomyNR7Aim: adjuvantNR7Aim: palliative
Scheme:
5-FU, cisplatin, carboplatin, mitomycin C, vincristine, etoposide, and docetaxel, either as single agents or in combined regimes		NR0
Sawada et al. 2018 [77]4Simple vulvectomyNR0--0--9 (topical imiquimod)
Hiratsuka et al.
2018 [78]		0--1Aim: radical
Total dose/Fr: 25 Gy-Eq
Technique: BNCT
Volume: NR		Acute moderate skin erosion and dysuria0--0
Hsieh et al.
2018 [79]		6WLE

Margin status: NR		NRNRAim: rescue RT
Total dose/Fr and technique: external beam vulvar radiation 56 Gy + interstitial brachytherapy to 30 Gy.
Volume: perineum and the left-side inguinal nodes + interstitial brachytherapy		NRNRAim: palliative
Scheme:
1° line CT: 6 cycles of carboplatin AUC 5 + paclitaxel 175 mg/m2 q21, TZB from cycles 2 to 6 + TZB 5 cycles maintenance

2° line CT: T-DM1 3.6 mg/kg q21 for 6 cycles		2° line CT: G1 fatigue and bleeding, (intermittent vaginal bleeding, hematuria, epistaxis, and gum bleeding, which started after cycle 2)0
Nitecki et al.
2018 [80]		42WLE (19%)
Partial SV (26.2%)
RV (47.7%)
Vulvar mapping (7.1%)

Margin status: R+ in 3 cases (7.1%)		NR0--0--0
Rioli et al.
2018 [81]		0--0--0--13
Kato et al. 2018 [82]0- 0--8Aim: palliative
Scheme:
5-fluorouracil (500 mg/body, 7 days/week) and cisplatin (5 mg/body 5 days/week)		-0
Cai et al. 2018 [83]0--0--8Aim: palliative
Scheme:
docetaxel 60 mg/m day 1; cisplatin 25 mg/m day 1–3		-0
Bouceiro-Mendes et al.
2019 [84]		1Local surgical excision followed by WLE ➝ total Vu with fasciocutaneous flap reconstruction.

Margin status: R1 (both excision); R0 (Vu)		NR1Aim: rescue RT at 4 years after surgery
Total dose/Fr: 59.4 Gy
Technique: NR
Volume: NR		None0--0
Loiacono et al.
2019 [85]		24WLE (25%), SV (33.3%), extended Vu (41.7%)

Margin status: R1 in 12 patients		Wound dehiscence (4) and 1 case urethral stenosis (1)0--0--0
Mujukian
et al. 2019 [86]		1Wide local excision and then radical excision with a split skin graft reconstruction 6 years after the original diagnosisNR0--0--1 (topical imiquimod)
Molina et al. 2019 [87]3Local excisionNR0--0--3
(topical imiquimod 5% in all, photodynamic therapy in case 1)
Hirai et al. 2019 [88]0--0--5CDDP (30 mg/m2), EPI (50 mg/m2), and TXL (120 mg/m2) per cycleEmatotoxicity (100%)0
van der Linden et al.
2019 [89]		74ni-VPD (51): 64.7% WLE, 9.8% HV, 23.5% (skinning) Vu
mi-VPD (10): NR
i-VPD (13): 37.5% skinning Vu, 12.5% HV, 31.3% WLE, 29.2% groin surgery.

Margin status:
ni-VPD: R+ in 82.4%
mi-VPD: R+
i-VPD: R+ in 76.9%		NR3 (1 in mi-VPD group, 2 in i-VPD group)NRNR1In i-VPD group
Aim: palliative
Scheme: NR		NR21
Panoskaltsis et al. 2019 [90]1WLENR1Aim: adjuvant-0--0
Nasioudis et al. 2020 [91]2412WLE (46.9%)
PV (34.1%)
RV (4.2%)
Total vulvectomy (6.4%)
NR (6.8%)

Margin status: R+ in 52.7%		NR35NRNR0--121 (immunotherapy)
Bartoletti et al.
2020 [92]		4Case 1: vulvo-perianal WLE with left colostomy ➝ ileo-inguinal LA and enlargement of previous perineal resection
Case 2: SV ➝ vulvar resection ➝ urethral relapse excision ➝ new resection of the urethral meatus
Case 3: SV with positive margins ➝ RV with the excision of the perineum, perianus, and part of the gluteal muscle ➝ bulky inguinofemoral LNs excision
Case 4: laser vaporization of the anal and perianal mucosa and a SV with skin grafts, with two large triangular flaps bilaterally (V-Y plastic) ➝ skinning Vu of the anterior hemi-vulva with plastic reconstruction and perianal/anal excision

Margin Status: NR		NR2Aim: palliative RT after surgery
Total dose/Fr:
Case 2: 30 Gy
Case 3: 30 Gy/10 fr
Technique:
Case 2: NR
Case 3: whole brain radiation
Volume:
Case 2: pelvis
Case 3: brain		NR4Aim: palliative after surgery
Scheme:
Case 1: w-paclitaxel + w-TZB for 9 months, then maintenance with 3-w-TZB for 1 year ➝ re-challenge with w-paclitaxel and TZB for 7 months, then maintenance with 3-w-TZB for 7 months ➝ TZB emtansine for 2 months, ongoing
Case 2: 3-w-cisplatin for 2 cycles➝ w-paclitaxel + w-TZB for 5 months
Case 3: w-paclitaxel for 4 total cycles + w-TZB for 4 months, then 3-w-TZB for 11 months ➝ 3-w-TZB and carboplatin for 1 cycle
Case 4: 3-w-TZB ➝ w-paclitaxel and 3-w-TZB		Case 1: G3: neutropenia Case 2: G2: anemia, onychopathyCase 3: G1: fatigue, constipation, nausea, anemia and alopecia, G2: neurotoxicityCase 4: G2: neurotoxicity3
Bruce et al.
2020 [93]		1Left RV ➝ bilateral sentinel LN biopsy ➝ left inguinal LA.

Margin status:
R0 in adenocarcinoma area, R+ in EMPD area		NR1Aim: adjuvant
Total dose/fr: 5940 cGy/33 fr
Technique: NR, but in combination with CT
Volume: pelvis		NR1Aim: adjuvant
Scheme: 2 cycles of carboplatin + paclitaxel ➝ delivery ➝ CT-RT with w- cisplatin ➝ TZB 1 year		NR0
Noel et al.
2020 [94]		1Left RV with left groin dissection, laparoscopic left inguinal LN dissection, and perineal V-Y plasty repair

Margin status: NR		NR1Aim: adjuvant
Total dose/Fr: NR
Technique: NR
Volume: NR		NR0--0
Kilts et al. 2020 [95]1034SurgeryNR0--0--0
Rathore et al.
2020 [96]		0--0--0--1
Sarkar et al.
2020 [97]		1WLE

Margin status: R0 inferior, R+ superior and lateral		NR1Aim: adjuvant
Total dose/fr: 50 Gy/28 fr
Technique: NR
Volume: groin, bilateral inguino-femoral and pelvic LNs		NR0--0
Sopracordevole et al.
2020 [98]		7WLE (57%), superficial total Vu (29%), skinning Vu (14%)

Margin status: R+ in 3 cases (42.9%)		NR3Aim: prior treatment
Total dose/Fr: NR
Technique: NR
Volume: NR		NR0--0
Stasenko et al.
2020 [99]		19NRNR0--1Aim: palliative
Scheme: PIK3CA inhibitor in clinical trial		NR7
Liang et al.
2021 [100]		38ni-VPD (29): PV (48%), SV (28%), RV (14%), WLE (10%)

mi-VPD (8): PV (88%), SV (12%)

i-VPD (1): NR

Margin status:
ni-VPD: R+ in 51.7%
mi-VPD: R+ in 12.5%
i-VPD: NR		NR1Aim: adjuvant, concurrent CT-RT
Total dose/Fr: NR
Technique: NR
Volume: NR		NR1Aim: adjuvant, concurrent CT-RT
Scheme: NR		NR0
Hirata et al.
2021 [101]		1Surgical resection of vulvar and perineal tumors

Margin status: NR		NR0--1Aim: palliative
Scheme: docetaxel, for more than 16 months		NR0
Kosmidis et al.
2021 [102]		2WLE

Margin status: R0		None0--0--0
Mazzilli et al.
2021 [103]		1NRNR---0--0
Preti et al.
2021 [104]		95WLE (41–44%)
HV (26–27%)
TV (13–16%)

Margin status: R+ in 91.7%		NR0--0–-27
Liu et al. 2021 [105]5425 extended resection (8 experienced unilateral or bilateral inguinal lymph node metastasis and underwent inguinal lymph node dissection),
29 palliative resection

Margin status: NR		NR0--0--0
Ferrara et al.
2021 [106]		0--0--0--10
Bajracharya et al.
2022 [107]		1RV + bilateral groin dissection + bilateral gracilis pedicles flap + urethral and introitus reconstruction

Margin status: R0		NR1Aim: adjuvant
Total dose/Fr: NR
Technique: NR
Volume: NR		NR0--0
Wang et al.
2022 [108]		0--0--0--2
Borella et al. 2022 [109]0--0--0--55
Van der Linden et al. 2022 [110]0--0--0--24
➝ = for relapse; AWD = alive with disease; Cr = case report; CR = complete response; Cs = case series; CT = chemotherapy; DCR = disease control rate; DID = died of intercurrent disease; DOD = died of disease; HV = hemivulvectomy; i-VPD = invasive vulvar Paget’s disease; LA = lymphadenectomy; LFU = lost to follow-up; LN = lymph node; MAL-PDT = methyl 5-aminolevulinic photodynamic therapy; mi-VPD = microinvasive vulvar Paget’s disease; NED = no evidence of disease; ni-VPD = noninvasive vulvar Paget’s disease; NR = not reported; PD = Progressive disease; PPS = prospective pilot study; PR = partial response; pts = patients; PV = simple partial vulvectomy; R = residual disease; Ra = retrospective analysis; RT = radiotherapy; RV = radical vulvectomy; SV = simple vulvectomy; TZB = trastuzumab; Vu = vulvectomy; w = weekly; WLE = wide local excision, 5-FU = 5-fluorouracil.
Table
Table 3. Outcomes and recurrence treatments.
Table 3. Outcomes and recurrence treatments.
ReferenceMedian FUDCR/Recurrence RatePFSOSRecurrence Treatment
Systemic PDLocal Recurrence
Kodama et al. 1995 [16]NRNRni-VPD + mi-VPD: 65.7%

i-VPD: 27.7%		NRi-VPD: CT, RTni-VPD: CT, RT, surgery

mi-VPD: surgery

i-VPD: CT, RT, surgery
Fishman et al. 1995 [17]NRMean time to recurrence:
  • negative margins: 4.4 (3–12) years
  • positive margins: 1.4 (1–11.8) years
Recurrence rate: 35.7%		NRNR-Surgery
Yoshitatsu et al. 1997 [18]6 yearsCR6 years6 years-Surgery
Goldblum et al. 1997 [19]9 yearsni-VPD: 4 pts with local recurrence from 25 months to 12 years

i-VPD: 1 died of the disease		NRNR-Surgery
Fanning et al.
1999 [20]		7 years (3–23)Recurrence rate: 34% at a median of 3 (0.6–15) years3 yearsNR--
Henta et al.
1999 [21]		NRNearly local CRNRNR--
Murata et al.
1999 [22]		NRPR to RT → died of the diseaseNR13 months--
Louis-Sylvestre et al.
2001 [23]		5.1 years (1–12.1)Mean time to recurrence:
  • After laser alone: 1 ± 0.6 years
  • After limited excision + peripheral laser: 1.9 ± 1.5 years
  • After wide excision alone: 2.7 ± 1 years
Recurrence rates at 1 year:
  • After laser alone: 67%
  • After limited excision + peripheral laser: 33%
  • After wide excision alone: 23%
NRNR--
Wilkinson et al.
2002 [6]		NRNRCase 1: NR
Case 2: no PD at 9 months
Case 3: NR		Case 1: NR
Case 2: still alive
Case 3: NR		--
Tebes et al.
2002 [24]		13.5 months
(1–216)		Mean time to recurrence: 30 months (3–89)NRNR-Surgery
Luk et al. 2003 [25]NRNR10 months15 months--
Wang et al. 2003 [26]NRCRNRNR-Imiquimod
Chin et al. 2004 [27]NR-8 years---
Zawislak et al. 2004 [28]3 monthsCR----
Bhattacharya et al. 2005 [29]8 yearsNRNRNR-Surgery
Raspagliesi et al.
2006 [30]		1–5 monthsDCR: 100% (CR 57.1%, PR 42.9%)NRNR--
Yanagi et al. 2007 [31]5 months (case 1) and 2 years (case 2)CRNRNR--
Hatch et al.
2008 [32]		12 months
6 months		CRNRNR--
Karam et al.
2008 [33]		NRNRNRNR-Imiquimod, TZB
Challenor et al. 2009 [34]4 months
3 months		CRNR3.5 months--
Sendagorta et al. 2010 [35]22 months
(20–26)		CRNRNR--
Shaco-Levy et al.
2010 [36]		NRRecurrence rate: 32%NR43% NED, 43% DID, 3% LFU, 2% DOD with invasive adenocarcinoma, 9% AWD--
Roh et al. 2010 [37]36.6RR: 56%NRNRNRNR
Anton et al. 2011 [38]NRCRNRNR--
Feldmeyer et al. 2011 [39]12 monthsCR12 months12 months--
Hanawa et al.
2011 [40]		NRPR after 4 courses of CT, then PDNRNRRT in inguinal LNs and primary lesionRT
Jones et al. 2011 [41]NRNRNRNRNRNR
Tonguc et al. 2011 [42]24 monthsCR24 months24 months-Surgery, imiquimod
Mendivil et al. 2012 [43]53 monthsRR: 56.2%NRNRNRNR
Al Yousef et al. 2012 [44]NRPersistence of disease: 100%NRNRNRNR
Baiocchi et al. 2012 [45]30.5 months
(21–40)		DCR: 100% (PR: 25%; CR: 75%)
Recurrence rate: 25%		NR30.5 months--
Wakabayashi et al.
2012 [46]		NRRecurrence5 years after 1° surgery, 3 years after 2° surgeryNR3-w-TZB-
Cai et al.
2013 [47]		NRRecurrence rate: 34.3%NR
  • Intraepithelial cases: 24.5 months
  • Invasive cases: 70.8 months
  • Cases with adnexal adenocarcinoma: 21.3 months
Surgery (12)

RT (3)		-
Choi et al. 2013 [48]38 months
(34–46)		CR: 100%38 months38 months--
Gavriilidis et al.
2013 [49]		7 monthsNRNEDNED--
Sanderson et al. 2013 [50]18 months
(12–24)		CR: 50%
PD: 33.3%
Recurrence rate: 16.6%		NR18 months--
De Magnis et al.
2013 [51]		76.9 monthsRecurrence rate: 44.1%45.7 monthsNR-WLE
Treglia et al. 2013 [52]NRDCR: 3 years3 years3 yearsChemotherapyChemotherapy
Magnano et al. 2013 [53]NRDCR: 2 monthsNRNRMAL-PDT (3 treatments) + topical tretinoin 0.05% and vitamin E with CR at time of writing (6 months)
Marchitelli et al.
2014 [54]		18 monthsCR: 90%NR14.4 months--
Liu et al.
2014 [55]		43.6 monthsRecurrence rate: 43.5%12.7 monthsNR--
Luyten et al.
2014 [56]		14.4 monthsNRNR14.4 months--
Carrozzo et al. 2014 [57]34 monthsAll patients showed complete remission of the disease without histological evidence of tumor at the end of the treatments *34 months34 months* Second course of brachytherapy in persistent/recurrent disease-
Frances et al. 2014 [58]NRCR at 2 weeks after the end of the treatmentsNRNR--
Hata et al. 2015 [59]38 months (range, 2–109 months)3- and 5-year overall local control: 100%3-year distant metastasis-free rates: 66%
5-year distant metastasis-free rates: 55%		3-year OS: 92%; 5-year OS: 62%
3-year cause-specific survival rates: 92%
5-year cause-specific survival rates: 71%		--
Asaka et al. 2015 [60]32 monthsCRNRStill alive--
Sopracordevole et al. 2016 [61]79.5 monthsRecurrence rate: 29.6%NRNR--
Cowan et al.
2016 [62]		35 monthsDCR: 75% (CR)
Of the 6 pts for whom a CR was achieved, VPD recurred in 4 (67%)		NRNR--
Fan et al. 2016 [63]70 monthsRecurrence rate 11%NRNR--
Nagai et al. 2016 [64] Recurrence rate: 50%8 months25 months--
Onaiwu et al.
2016 [65]		73.9 monthsRecurrence rate: 58.4%NR73.2 months-Excision + local imiquimod
Hillmann et al. 2016 [66]NRNRNRNR--
Liau et al. 2016 [67]NRNRNRNR-Imiquimod treatment
Total duration of the treatment: 22-100-16 months
Jeon et al. 2016 [68]NRNRNRNR-
Dogan et al. 2017 [69]6 monthsCR6 months6 months--
Vicentini et al. 2017 [70]NRNRNRNR--
Parashurama et al. 2017 [71]NRRecurrence rate: 67%NR8 years--
Konstantinova et al. 2017 [72]NRNRNRNR--
Mota et al. 2017 [73]NRNRNRNR--
Long et al. 2017 [74]5 yearsRecurrence rate: 37.7%56.1% at 5 yearsNR--
Kato et al. 2018 [75]5.7 months
11 months		18 weeks after surgery
10 months after surgery		NR5.7 months
11 months		--
Borghi et al. 2018 [76]57 monthsRecurrence rate: 60%, with a mean time to first recurrence of 20 (range, 5–36) monthsNRInvasive group: 70% at 48 months--
Sawada et al. 2018 [77]46 monthsDCR: 100% (56% CR, 44% PR)NRNR--
Hiratsuka et al.
2018 [78]		NRDCR: CR in 6 months3.2 years3.2 years (DID)--
Hsieh et al.
2018 [79]		NRDCR: CR after 1° line CT, CR after 6 T-DM1 cycles7.0 months with 1° line CT followed by TZB maintenance; 6.0 months with T-DM1NRTDM16 excisional procedures, 3 laser ablations, several courses of topical imiquimod treatment, RT
Nitecki et al.
2018 [80]		45.8 monthsRecurrence rate: 2 months (1–6)28.7 months
(0–169)		NR-Weekly cisplatin + palliative radiation
Rioli et al.
2018 [81]		38 monthsRecurrence rate: 7%NRNR--
Kato et al. 2018 [82]-DCR: 75% (50% PR, 25% SD)
PD: 25%		25.0 weeks77.4 weeks--
Cai et al. 2018 [83]53 monthsDCR: 100% (50% PR, 50% SD)9.9 months28.9 months--
Bouceiro-Mendes et al.
2019 [84]		4 yearsDisease control: 4 years post-Vu; 3 months post-RT4 years4 years-RT 4 years after surgery; imiquimod after 3 months post-RT
Loiacono et al.
2019 [85]		NRRecurrence rate: 33%NRNR-Surgery
Mujukian
et al. 2019 [86]		NRNRNRNR-Surgery
Molina et al. 2019 [87]NRNRNRNR--
Hirai et al. 2019 [88]NR-20.1  months8 months--
van der Linden et al. 2019 [89]38 monthsRecurrence rate: 36.4%ni-VPD: 69.3 months i-VPD: 26.5 monthsNRCT-
Panoskaltsis et al. 2019 [90]18 monthsCRNR18 months--
Nasioudis et al. 2020 [91]66.5 monthsNRNRNR--
Bartoletti et al.
2020 [92]		NRNRNRNRCTSurgery
Bruce et al.
2020 [93]		NRNRNRNR--
Noel et al.
2020 [94]		NRNRNRNR--
Kilts et al. 2020 [95]NRNRNRFive-year cancer specific survival (CSS) was 95.5% and was associated with the stage. Compared to patients with localized disease, patients with distant metastases had dramatically worse CSS (HR: 85.8 (31.8–248) p < 0.0001).
Vital status (120 months): alive, 569 (94.7%); died, 32 (5.3%)		--
Rathore et al.
2020 [96]		NRNR1 month1 month--
Sarkar et al.
2020 [97]		NRDCR: 18 months18 monthsStill alive--
Sopracordevole et al.
2020 [98]		NRDCR: 24 monthsNRNR-Surgery (9 pts, 90%); third treatment for recurrence (4 pts, 40%), a quarter treatment (2 pts, 20%), fifth treatment for recurrence of disease (1 pt, 10%)
Stasenko et al.
2020 [99]		8 monthsRecurrence rate: 62%NRNRPIK3CAi (1 pt 6%)Surgery (10 pts, 63%), imiquimod (4 pts, 25%), topical 5-FU (1 pt 6%).
Liang et al.
2021 [100]		NRNRNRNR-Surgical excision
Hirata et al.
2021 [101]		NRNRNRNR--
Kosmidis et al.
2021 [102]		NRNRNRNR--
Mazzilli et al.
2021 [103]		NRNRNRNR--
Preti et al.
2021 [104]		94.6 monthsRecurrence rate: 73%NR39 months--
Liu et al. 2021 [105]2 years and at most 10 yearsNRNRNR--
Ferrara et al.
2021 [106]		12 monthsRecurrence rate: 60%NR12 months--
Bajracharya et al.
2022 [107]		24 months-24 months24 months--
Wang et al.
2022 [108]		17.4 monthsRecurrence rate: 36.4%

DCR:
Case 1: relapse at 24 month (FU 27 months).
Case 2: no relapse (FU 14 months)		24 monthsNR--
Borella et al. 2022 [109]66 monthsNRNR31 months--
Van der Linden et al. 2022 [110]31 monthsRecurrence rate: 34.8%NR31 months--
➝ = for relapse; AWD = alive with disease; Cr = case report; CR = complete response; Cs = case series; CT = chemotherapy; DCR = disease control rate; DID = died of intercurrent disease; DOD = died of disease; HV = hemivulvectomy; i-VPD = invasive vulvar Page’s disease; LA = lymphadenectomy; LFU = lost to follow-up; LN = lymph node; MAL-PDT = methyl 5-aminolevulinic photodynamic therapy; mi-VPD = microinvasive vulvar Paget’s disease; NED = no evidence of disease; ni-VPD = noninvasive vulvar Paget’s disease; NR = not reported; PD = Progressive disease; PPS = prospective pilot study; PR = partial response; pts = patients; PV = simple partial vulvectomy; R = residual disease; Ra = retrospective analysis; RT = radiotherapy; RV = radical vulvectomy; SD, stable disease; SV = simple vulvectomy; TZB = trastuzumab; Vu = vulvectomy; w = weekly; WLE = wide local excision.
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Caruso, G.; Barcellini, A.; Mazzeo, R.; Gallo, R.; Vitale, M.G.; Passarelli, A.; Mangili, G.; Pignata, S.; Palaia, I. Vulvar Paget’s Disease: A Systematic Review of the MITO Rare Cancer Group. Cancers 2023, 15, 1803. https://doi.org/10.3390/cancers15061803

AMA Style

Caruso G, Barcellini A, Mazzeo R, Gallo R, Vitale MG, Passarelli A, Mangili G, Pignata S, Palaia I. Vulvar Paget’s Disease: A Systematic Review of the MITO Rare Cancer Group. Cancers. 2023; 15(6):1803. https://doi.org/10.3390/cancers15061803

Chicago/Turabian Style

Caruso, Giuseppe, Amelia Barcellini, Roberta Mazzeo, Roberta Gallo, Maria Giuseppa Vitale, Anna Passarelli, Giorgia Mangili, Sandro Pignata, and Innocenza Palaia. 2023. "Vulvar Paget’s Disease: A Systematic Review of the MITO Rare Cancer Group" Cancers 15, no. 6: 1803. https://doi.org/10.3390/cancers15061803

APA Style

Caruso, G., Barcellini, A., Mazzeo, R., Gallo, R., Vitale, M. G., Passarelli, A., Mangili, G., Pignata, S., & Palaia, I. (2023). Vulvar Paget’s Disease: A Systematic Review of the MITO Rare Cancer Group. Cancers, 15(6), 1803. https://doi.org/10.3390/cancers15061803

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