Invasive extramammary Paget’s disease and the risk for secondary tumours in Europe

doi:10.1016/j.ejso.2011.12.008

European Journal of Surgical Oncology (EJSO)

Volume 38, Issue 3, March 2012, Pages 214-221

https://doi.org/10.1016/j.ejso.2011.12.008 Get rights and content

Abstract

The aim of this study was to determine the incidence and survival of Extramammary Paget’s disease (EMPD) and to describe the possible increased risk of tumours after EMPD.

All invasive cases diagnosed between 1990 and 2002 were selected from the RARECARE database. Incidence was expressed in European standardized rates. Relative survival was calculated for the period 1995–1999, with a follow-up until 31st December 2003. Standardized incidence ratios of second primary tumours were calculated to reveal possible increased risk after EMPD.

European age standardized Incidence of EMPD within Europe is 0.6 per 1000,000 person years. Five-year relative survival for invasive EMPD was 91.2% (95%CI; 83.5–95.4), 8.6 percent of the EMPD patients developed other malignancies. The highest increased risk of developing a second primary tumour was found in the first year of follow-up (SIR:2.0 95%CI; 1.3–2.9), living in the South European region (SIR:2.3 95%CI; 1.5–3.5) or being female (SIR:1.5 95%CI; 1.1–1.9). Female genital organs displayed greatest increased risk of developing a second primary tumour after EMPD (SIR:15,1 95%CI; 0.38–84.23).

Due to the increased risk of a second primary tumour after EMPD a thorough search for other tumours during their follow-up is recommended.

Introduction

Extramammary Paget’s Disease (EMPD) is a rare tumour whose precise incidence is not clear¹ because of the non specific clinical findings of EMPD, which easily lead to wrong diagnoses.² EMPD mostly affects individuals between the ages 50 and 80 years and is more frequently diagnosed in women than men.²

In 1874, James Paget described Mammary Paget’s Disease (MPD) as a chronic disease of the skin of the nipple and areola only.³ In 1888, during a meeting of the Pathological Society of London, Crocker presented a special case of MPD, which was located on the scrotum and penis in a goldsmith, aged sixty years old.⁴ In 1889, Crocker officially described EMPD as a special form of ductal carcinoma involving other parts of the body than the breast, as first described by James Paget.³ The clinical symptoms, eczema-like lesions, had clinical and histological features similar to those of MPD.⁴ Histological EMPD is described as a cutaneous adenocarcinoma with typical Paget cells,5, 6, 7 i.e. large cells with large nuclei and abundant cytoplasm which usually stain pale. It occurs with preference in skin zones rich of apocrine glands, but can occur anywhere on the skin or mucosa. Its most common visible symptom of EMPD is signs of pruritus,⁶ and it occurs mainly among the elderly, with a higher risk seen in Caucasian women in their 60s and 70s.⁸

Since a possible association with other malignancies, before or after diagnosis of EMPD, has been described,7, 9 a thorough physical examination with a 5-year follow-up after diagnosis has been recommended for patients being diagnosed with EMPD, to discover other regional rectal, urothelial or vulvar malignancies at time of diagnoses or during follow-up.7, 10 The location of the underlying internal malignancy is often linked to the location of the EMPD: a perianal location may signify a malignancy of the gastrointestinal tract and a penile, scrotal or groin location may be associated with an adenocarcinoma of the genitourinary tract.⁵

As it is a rare cancer, no clear guidelines have been established for diagnosis, treatment and follow-up of patients, presenting a challenge for clinical practice, and research is often confined to case reports or small retrospective studies.

The RARECARE database, a European database that contains data from a large group of European cancer registries (CRs), has been developed to describe the burden of rare cancers and allows comparison of different European regions. Furthermore, it allows comparison between countries with different Gross Domestic Products (GDP) and Total National Expenditure on Health (TNEH), which could influence the survival.

The aim of this population-based study was to describe the incidence, survival and risk of developing other malignancies in patients with EMPD within Europe based on the RARECARE database.

Section snippets

Patients

Data on patients diagnosed with invasive EMPD were provided by European population-based CRs which participated in the RARECARE project. Only registries with detailed data on morphology available were included, resulting in 63 population-based CRs from 16 different European countries. Period coverage of the different registries participating in the RARECARE project is described in Table 1. These were divided into four regions following the EUROCARE project¹¹; Northern Europe (Sweden, Norway and

Incidence

In the 13-year period, 871 cases of EMPD were registered as primary malignancy (male to female ratio 1:2.8; Table 2). The median age at diagnosis for EMPD for females (n = 640) was 74 years (range 36–96 years) which is similar to the median age for males (n = 231) (range 16–95 years).

The most frequent parts of the body in which EMPD occurred were the anus and anal canal (n = 40), extragenital skin (n = 178), vulva(n = 533) and other and unspecified male genital organs (n = 72) (Table 2) For

Discussion

This study compiles a unique large number of patients diagnosed with EMPD using the data of the RARECARE database, enabling coverage of a mean population of 90,163,609 people over 13 years. Siesling et al. and Pierie et al. presented data on invasive EMPD as well EMPD in situ, reporting a distribution of 1:3.7 and 1:1.8 respectively.7, 18 We had to exclude the EMPD in situ for analyses as we have no information on how the different cancer CRs distinguished the EMPD in situ from invasive EMPD;

Conflict of interest

None.

Acknowledgements

The authors want to thank the European Commission for their financial contribution to the RARECARE project. Also we want to thank the RARECARE workgroup for their contribution of data.

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Extramammary Paget disease is an uncommon slow growing intraepithelial malignant neoplasm. It can be classified into primary and secondary subtypes, with secondary subtype associated with underlying malignancy. Extramammary Paget disease of the penoscrotal region is extremely rare with very limited literature available describing its clinicopathologic characteristics. We present 6 cases of penoscrotal EMPD diagnosed at our academic medical center over a 20 year period. These included 5 cases of scrotal EMPD and 1 case of penile EMPD. The mean age at diagnosis was 68.6 yrs. (Range 61–78 years), One case of scrotal EMPD had history of renal cell carcinoma and prostatic adenocarcinoma, while one other case presented as recurrent EMPD with initial disease in the left groin. EMPD in the glans penis was associated with a history of urothelial carcinoma in the ureter with pagetoid spread. 3 cases had no progression of the disease till recent follow up, 2 were lost to follow up while 1 case rapidly deteriorated resulting in death. This case had bone metastatic and associated peritoneal carcinomatosis. Thus, Extramammary Paget disease of the penoscrotal area is extremely rare, can be primary or associated with visceral malignancies and usually tends to present at an older age. Peritoneal spread and distant metastasis are associated with rapid progression of the disease.
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Extramammary Paget's disease (EMPD) is a rare cutaneous malignant disease. Due to its rarity, there is a paucity of data regarding best treatment strategy. EMPD primarily affects apocrine gland-bearing skin areas such as the vulva, scrotum, and penis. Our objective was to provide a present-day rationale for diagnosis, pathogenesis, and treatment of EMPD with a focus on recent progress in workup and management of the disease.
Literature on EMPD until February 2022 was assessed through PubMed, MEDLINE databases, and Google scholar. A narrative review of the most relevant articles was provided.
EMPD usually presents with indolent growth while usually being diagnosed primarily as carcinoma in situ. The foundation of EMPD treatment centers around prompt and accurate diagnosis, wide local or Mohs micrographic surgical excision with proper management towards the margin status, and careful consideration for lymphadenectomy in patients with regionally positive disease. Conventional chemotherapies are alternative treatments modality for patients with distant metastases; however, they sometimes have suboptimal efficacy. At present, there is no agreement regarding adjuvant or systemic therapies, although recent studies have shown several insights into the molecular pathogenesis, tumor biology, and genomics of the development and advancement of EMPD, which may lead to novel and targeted treatment approaches for metastatic EMPD in the future.
Patients with EMPD should seek care from physicians with expertise in disease management and patient counseling. These patients should be surveilled with close follow-up to evaluate them for disease recurrence or progression. Global collaborations with groups such as the Global Society for Rare Genitourinary Tumors, and especially patient support groups are crucial in designing clinical trials to help elucidate more robust data in this orphan disease.
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Vulvar Paget's disease (VPD) is a rare neoplasm with high recurrence rates even after surgical treatment.
Imiquimod topical cream is a promising therapy; however, experience with it is limited to small series or case reports.
This study aims to analyze the effectiveness and safety of topical imiquimod in a large cohort of patients with VPD.
Fifty-five cases of histologically proven- VPD treated with topical imiquimod at the Gynecologic and Obstetric Division 1 U, S. Anna Hospital, University of Turin were retrospectively reviewed.
We investigated the potential factors related to clinico-pathological response to imiquimod using univariate and multivariate logistic regression to estimate odds ratios (ORs).
Four women discontinued the treatment due to side-effects. Of the remaining 51 (42 in situ tumors, and 9 micro-invasive tumors) who completed treatment, 22 (43%) achieved a complete clinico-pathological response. Among the women who had a complete response, there were no cases of recurrence (mean follow-up: 66 months).
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Imiquimod can be safely used for the treatment of VPD, even for micro-invasive tumors. Furthermore, we report some potential predictors of treatment response.
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Citation Excerpt :
Invasive EMPD can be challenging to diagnose and can histologically mirror carcinomas with apocrine immunophenotypes.23 Evidence-based clinical practice guidelines21 recommend screening for internal malignancies that may be contiguous (7.9%-23.9%) or discontiguous (8.6%-46.1%)2,24-28 with cutaneous EMPD. Genital EMPD has been associated with urogenital malignancy and perianal EMPD with gastrointestinal and/or colorectal cancer.21
To describe local recurrence rates and patient-reported outcomes when Mohs micrographic surgery with cytokeratin-7 immunostains (MMS-CK7) is included in the interdisciplinary management of extramammary Paget's disease (EMPD)
A retrospective study was conducted of EMPD treated with MMS-CK7 as part of an interdisciplinary team at an academic medical center between 2009 and 2016. Local recurrence rates and patient-reported outcomes were determined by record review and patient surveys.
Twenty tumors in 19 patients were treated using MMS-CK7. After MMS-CK7 defined clear microscopic margins, 75% (15/20) of tumors underwent excision or reconstruction by a surgical colleague. Internal malignancy screening was performed by multiple specialties in 17 patients, with 1 associated malignancy of prostate cancer detected. No local recurrence was detected with a mean follow-up of 75.2 months. Most patients were satisfied with appearance (18/19, 95%) and function (16/19, 84%) after surgery.
Interdisciplinary teams that include MMS-CK7 can treat EMPD with low local recurrence rates, high patient satisfaction, and thorough internal malignancy screening.

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^f: On behalf of the RARECARE Working Group (Members of the RARECARE working group can be seen in Appendix).

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Invasive extramammary Paget’s disease and the risk for secondary tumours in Europe

Abstract

Introduction

Section snippets

Patients

Incidence

Discussion

Conflict of interest

Acknowledgements

J Am Acad Dermatol

Eur J Surg Oncol

Eur J Cancer

J Am Coll Surg

Extramammary Paget’s disease

BJOG

The Roswell Park Cancer Institute experience with extramammary Paget’s disease

Br J Dermatol

On disease of mammary areola preceding cancer of the mammary gland

St Barth Hosp Rep

Paget’s disease affecting the scrotum and penis

Trans Pathol Soc Lond

Mammary and extramammary Paget’s disease

J Clin Pathol

Extramammary Paget’s disease: a report of 22 cases in Chinese males

J Dermatol