CED
Clinical dermatology • Review article
Clinical and Experimental Dermatology
CPD
Risk stratification in extramammary Paget disease J. M. Cohen,1 S. R. Granter2 and A. E. Werchniak3,4 1 Harvard Medical School, Boston, MA, USA; 2Division of Dermatopathology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 3Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; and 4 Center for Cutaneous Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
doi:10.1111/ced.12690
Summary
Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best-understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of > 1 mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki-67, cyclin D1, Mucin 5AC and E-cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research.
Introduction Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma that involves regions with apocrine glands, such as the perineum, genitalia and perianal region.1,2 Cases of EMPD occurring in the axillae, cheek, abdomen and ear have also been reported.2 Rarely, EMPD can also involve the cutaneous apocrine glands.3 EMPD has been reported to be associated with internal malignancy in up to 29% of cases; genital EMPD is often associated with genitourinary carcinomas, while perianal EMPD is more frequently associated with gastrointestinal carcinomas.4 The most common site for EMPD is the vulva, accounting for approximately 65% of cases.2 The exact prevalence of EMPD is not known; however, it is Correspondence: Dr Andrew E. Werchniak, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115, USA E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 30 January 2015
ª 2015 British Association of Dermatologists
thought to be most common in postmenopausal white women.5 EMPD rarely metastasizes, but when it does, the most commonly observed sites of metastasis are lymph nodes and bone, while metastases to other sites such as the liver have also been reported.6–8 Multiple therapies are available to treat EMPD, and risk stratification may help physicians determine how aggressively any individual patient should be treated. In this report, we summarize the prognostic factors for patients with EMPD (Table 1). The most important factors are depth of invasion and the presence or absence of extracutaneous involvement. The presence or absence of certain genetic tumour markers is also useful, but the current availability of this type of analysis is somewhat limited. The site of involvement and patient demographics appear to be less important.
Prognostic factors Depth of invasion
Depth of invasion has been repeatedly reported as an important prognosticator in EMPD, and has been
Clinical and Experimental Dermatology (2015) 40, pp473–478
473
Risk stratification in extramammary Paget disease J. M. Cohen et al.
Table 1 Prognostic factors in extramammary Paget disease. Factors
Important characteristics
References
Depth of invasion
Noninvasive (confined to epidermis): low risk Micro-invasive (into papillary dermis): intermediate risk Invasive (into reticular dermis): high risk < 1 mm: low risk ≥ 1 mm: high risk Lymph node or distant metastases beyond the skin: high risk
Crawford et al. (1999)11 Hatta et al. (2008)9 Ito et al. (2012)6 Karam and Dorigo (2012)10 Lam and Funaro (2010);2 Zhu et al. (2009)7 Aoyagi et al. (2008);8 Hata et al. (2014);12 Hatta et al. (2004);15 Hatta et al. (2008);9 Ito et al. (2012);6 Karam and Dorigo (2012);10 Lam and Funaro (2010);2 Moretto et al. (2013);14 Nakamura et al. (2012);16 Zhang et al. (2010);13 Zhu et al. (2009)7 Aoyagi et al. (2008)8
Extracutaneous involvement
Genetic profile
Site of lesion
CK7+, CK20 , GCDFP 15+: more likely primary EMPD (no underlying malignancy) CK7+, CK20+, GCDFP 15 : more likely malignancy-related Expression of Ki-67 and cyclin D1: high risk for metastasis Expression of MUC5AC: high risk for metastasis; loss of E-cadherin: high risk for metastasis Anorectal disease: increased mortality risk
Demographic features
Increased age: increased mortality risk
Hata et al. (2014)12 Hatta et al. (2008)9 Zhu et al. (2009)7 Karam and Dorigo (2012);10 Lam and Funaro (2010)2 Karam and Dorigo (2012)10
CK, cytokeratin; GCDFP, gross cystic disease fluid protein.
divided into three categories in the literature: noninvasive, micro-invasive and deeply invasive disease.6,7,9,10 Noninvasive (in situ) disease is confined to the epidermis (Fig. 1), while micro-invasive disease invades into the papillary dermis (Fig. 2) and deeply invasive disease involves the reticular dermis (Fig. 3). Increasing depth of invasion has consistently been found to increase disease-specific mortality. Some studies have found a statistically significant difference between survival with noninvasive and micro-invasive disease, while others have not.6,7,9,10 However, deeply invasive EMPD has been clearly shown to portend a poorer prognosis than noninvasive disease.2,6,7,9,10 One study of 21 cases of vulvar EMPD suggested that tumours that are < 1 mm thick are associated with a better prognosis than those > 1 mm, but more precise information regarding depth-specific prognostication is lacking.11
inguinal lymph node involvement has better outcomes than bilateral inguinal lymph node involvement, based on a small number of patients.9 It is clear that as the disease progresses from localized to regional and from regional to distant, the disease-specific survival decreases. Positron emission tomography–computed tomography (PET-CT) scans have been found to be useful in determining the extent of disease and detecting distant metastases, but have a low sensitivity for detecting microscopic metastases.7 Sentinel lymph node biopsy (SLNB) has been explored in small studies, and has been found to be a safe and effective way of screening for extracutaneous metastasis.14–16 The indications for SNLB remain unclear, but it is seems that individuals with clinical evidence of involved lymph nodes or disease affecting the dermis may benefit from SNLB.15,16 There is no evidence to suggest that SNLB is necessary in noninvasive disease.15,16
Extracutaneous involvement
Genetic and protein expression profile
Involvement of sites beyond the skin, either lymph nodes or distant metastases, is an important predictor of outcome.2,6,9,10,12,13 Both distant metastases and metastases to regional lymph nodes are associated with worse outcomes than disease localized to the skin.2,6,8–10 One study has suggested that ipsilateral
Increasingly, genetic characteristics of tumours have become important prognostic factors. One study found that several genes, including Her-2, p53 and bcl-2, are expressed in multiple different types of EMPD lesions.8 However, Ki-67 and cyclin D1 were found to be expressed more frequently in invasive lesions than in
474
Clinical and Experimental Dermatology (2015) 40, pp473–478
ª 2015 British Association of Dermatologists
Risk stratification in extramammary Paget disease J. M. Cohen et al.
(a)
(b)
Figure 1 (a) In situ/intraepidermal extramammary Paget disease of the vulva showing scattered cells with abundant pale cytoplasm (haematoxylin and eosin, original magnification 9 400). (b) Cytokeratin 7 immunostaining highlights the neoplastic cells but does not stain background epidermis (original magnification 9 400).
lesions that remained noninvasive.8 Moreover, lesions expressing both Ki-67 and cyclin D1 were more likely to be invasive than lesions expressing either Ki-67 or cyclin D1.8 Another study found that MUC5AC was more likely to be expressed in invasive and metastatic lesions than in noninvasive lesions.12 The carcinoembryonic antigen (CEA) level has been found to be higher in individuals with metastatic EMPD than in those with nonmetastatic EMPD. Additionally, the level of CEA seems to mirror disease progression, and can be a useful marker of clinical course.7,9 Finally, the loss of expression of E-cadherin is more common in metastatic than in nonmetastatic EMPD.7 Site of lesion
The overwhelming majority of EMPD cases present as genital (vulvar or penoscrotal) disease.2 However, data suggest that anorectal disease may be somewhat more aggressive than genital and perineal disease. One
ª 2015 British Association of Dermatologists
study showed that although this association did not exist in multivariate analysis, patients with anorectal EMPD had a statistically significantly decreased mean disease-specific survival compared with those without anorectal involvement.10 Patient demographics
Risk stratification based on demographics is difficult, given that many of the published studies on EMPD describe a small number of fairly homogeneous patients. However, one study utilized the Surveillance, Epidemiology and End Results (SEER) database to study a large number of patients with invasive EMPD.10 They found that there was no significant difference in disease-specific survival between men and women, but they did find that age was positively associated with mortality.10 This finding contrasts with the findings of previous studies, probably because those studies included a small number of patients. Racial differences have not been studied.
Clinical and Experimental Dermatology (2015) 40, pp473–478
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Risk stratification in extramammary Paget disease J. M. Cohen et al.
Discussion Based on a synthesis of the existing EMPD literature, we discuss several important factors for the
Figure 2 Single nest of microinvasive carcinoma is visible, with
basal and parabasal layers of the epidermis present at the top of the photomicrograph (haematoxylin and eosin, 9 400).
(a)
prognosis of an individual with EMPD. Prognosis can be useful in both appropriate staging and selection of therapy for patients, and may also help in standardizing EMPD research. Overall, the strongest correlations with poor outcomes were related to depth of invasion and the presence or absence of metastases. Additionally, the genetic makeup of the tumour cells has been found to be an important indicator of outcome in some small studies. Weaker evidence exists to support a relationship between disease-specific survival and either the disease site or age of the patient. Based on these findings, patients with noninvasive (in situ) disease can be treated without SNLB or imaging. Patients with invasive disease should be considered for SNLB, particularly if there is invasion into the reticular dermis or beyond. PET scans should be reserved for those with a positive lymph node biopsy or with other symptoms or signs suggestive of more widespread involvement. While the factors discussed here are related to EMPD-specific survival, the presence of underlying malignancy is an important factor in management decisions. Data suggests that the presence of underlying malignancy does not change the risk of mortality from EMPD.6 However, individuals with systemic malignancy will require therapy for that malignancy in addition to therapy for EMPD. Individuals with EMPD, regardless of genotype, should undergo ageappropriate malignancy investigations, which may include colonoscopy; CT of the chest, abdomen and pelvis, cystoscopy; pelvic ultrasonography; Papanicolaou smear; colposcopy; and breast examination and mammography.2 (b)
Figure 3 (a) Deeply invasive extramammary Paget disease invading into the deep dermal collagen fibres (haematoxylin and eosin
9 400); (b) tumour cells highlighted by immunostaining for carcinoembryonic antigen (CEA) (original magnification 9 400).
476
Clinical and Experimental Dermatology (2015) 40, pp473–478
ª 2015 British Association of Dermatologists
Risk stratification in extramammary Paget disease J. M. Cohen et al.
We hope that this review succinctly summarizes some of the important prognostic factors in EMPD. The rarity of this disease makes it difficult to study. Some limitations to this study should be mentioned, including the small number of studies, the small sample sizes of relatively homogeneous patients, and that the search was restricted to publications that were in English and available through PubMed.
Conclusion Identification of risk factors that differentiate aggressive from indolent EMPD represents an important step in improving patient care and research. More data are needed to gain a better understanding of EMPD behaviour in a given clinical situation. Genetic tumour profiling represents a particularly promising area, and should be the focus of additional inquiry.
2
3
4
5
6
7
8
Learning points
9
• EMPD is an uncommon intraepithelial adeno-
carcinoma that can be indolent or quite aggressive. • Risk stratification in EMPD can be challenging. • The most important prognostic factors are depth of invasion and spread to extracutaneous sites. • Deeply invasive disease into the reticular dermis or depth of ≥ 1 mm have been found to indicate higher risk. • There is also a poorer prognosis associated with disease that has spread to extracutaneous sites, such as lymph nodes. • Tumour genetics, specifically expression of Ki-67, cyclin D1 and MUC5AC and loss of E-cadherin, have been shown to increase risk of extracutaneous spread, and may represent an important emerging factor. • There is less evidence supporting the importance of age and site of lesion in risk stratification of EMPD.
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11
12
13
14
15
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review of the literature emphasizing management. Dermatol Surg 2013; 39: 69–75. Lam C, Funaro D. Extramammary Paget’s disease: summary of current knowledge. Dermatol Clin 2010; 28: 807–26. Vincent J, Taube JM. Pigmented extramammary Paget disease of the abdomen: a potential mimicker of melanoma. Dermatol Online J 2011; 17: 13. Chanda JJ. Extramammary Paget’s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13: 1009–14. Wang X, Yang W, Yang J. Extramammary Paget’s disease with the appearance of a nodule: a case report. BMC Cancer 2010; 10: 405. Ito Y, Igawa S, Ohishi Y et al. Prognostic indicators in 35 patients with extramammary Paget’s disease. Dermatol Surg 2012; 38: 1938–44. Zhu Y, Ye DW, Yao XD et al. Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget’s disease. Br J Dermatol 2009; 161: 577–82. Aoyagi S, Akiyama M, Shimizu H. High expression of Ki67 and cyclin D1 in invasive extramammary Paget’s disease. J Dermatol Sci 2008; 50: 177–84. Hatta N, Yamada M, Hirano T et al. Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 2008; 158: 313–18. Karam A, Dorigo O. Treatment outcomes in a large cohort of patients with invasive Extramammary Paget’s disease. Gynecol Oncol 2012; 125: 346–51. Crawford D, Nimmo M, Clement PB et al. Prognostic factors in Paget’s disease of the vulva: a study of 21 cases. Int J Gynecol Pathol 1999; 18: 351–9. Hata H, Abe R, Hoshina D et al. MUC5AC expression correlates with invasiveness and progression of extramammary Paget’s disease. J Eur Acad Dermatol Venereol 2014; 28: 727–32. Zhang N, Gong K, Zhang X et al. Extramammary Paget’s disease of scrotum–report of 25 cases and literature review. Urol Oncol 2010; 28: 28–33. Moretto P, Nair VJ, Hallani SE et al. Management of penoscrotal extramammary Paget disease: case series and review of the literature. Curr Oncol 2013; 20: e311–20. Hatta N, Morita R, Yamada M et al. Sentinel lymph node biopsy in patients with extramammary Paget’s disease. Dermatol Surg 2004; 30: 1329–34. Nakamura Y, Fujisawa Y, Ishikawa M et al. Usefulness of sentinel lymph node biopsy for extramammary Paget disease. Br J Dermatol 2012; 167: 954–6.
References 1 Mengjun B, Zheng-Qiang W, Tasleem MM. Extramammary Paget’s disease of the perianal region: a
ª 2015 British Association of Dermatologists
Clinical and Experimental Dermatology (2015) 40, pp473–478
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Risk stratification in extramammary Paget disease J. M. Cohen et al.
CPD questions Learning objective To gain an understanding of the prognostic factors in extramammary Paget disease. Question 1
Extramammary Paget disease of the genitals is associated with which of the following types of internal malignancy? a) Haematological. b) Genitourinary tract. c) Upper gastrointestinal tract. d) Lower gastrointestinal tract. e) Melanoma. Question 2
A poor prognosis is associated with a depth of invasion greater than or equal to which of the following? a) 0.1 mm. b) 0.5 mm. c) 0.75 mm. d) 1.0 mm. e) 1.25 mm.
Question 3
Expression of Cyclin D1 is useful for predicting the presence of which of the following? a) Genital disease. b) Associated genitourinary malignancy. c) Invasive disease. d) Associated gastrointestinal malignancy. e) Noninvasive disease.
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Clinical and Experimental Dermatology (2015) 40, pp473–478
Question 4
Expression of MUC5AC is useful for predicting which of the following? a) Invasive and metastatic potential. b) Associated internal malignancy. c) Anal involvement. d) Tumour restricted to the papillary dermis. e) Rapid disease progression. Question 5
What is the role for positron emission tomography (PET) scans in extramammary Paget disease (EMPD)? a) There is never a role for PET Scans in EMPD. b) For detecting microscopic metastases. c) For determining extent of distant metastases. d) Only in anal EMPD. e) PET scans should be done in all patients with EMPD. Instructions for answering questions
This learning activity is freely available online at http://www.wileyhealthlearning.com/ced. Users are encouraged to • Read the article in print or online, paying particular attention to the learning points and any author conflict of interest disclosures • Reflect on the article • Register or login online at www.wileyhealthlearning.com/ced and answer the CPD questions • Complete the required evaluation component of the activity Once the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self-certified entry. This activity will be available for CPD credit for 2 years following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional period.
ª 2015 British Association of Dermatologists
Clinical dermatology • Review article
Clinical and Experimental Dermatology
CPD
Risk stratification in extramammary Paget disease J. M. Cohen,1 S. R. Granter2 and A. E. Werchniak3,4 1 Harvard Medical School, Boston, MA, USA; 2Division of Dermatopathology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 3Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; and 4 Center for Cutaneous Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
doi:10.1111/ced.12690
Summary
Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best-understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of > 1 mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki-67, cyclin D1, Mucin 5AC and E-cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research.
Introduction Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma that involves regions with apocrine glands, such as the perineum, genitalia and perianal region.1,2 Cases of EMPD occurring in the axillae, cheek, abdomen and ear have also been reported.2 Rarely, EMPD can also involve the cutaneous apocrine glands.3 EMPD has been reported to be associated with internal malignancy in up to 29% of cases; genital EMPD is often associated with genitourinary carcinomas, while perianal EMPD is more frequently associated with gastrointestinal carcinomas.4 The most common site for EMPD is the vulva, accounting for approximately 65% of cases.2 The exact prevalence of EMPD is not known; however, it is Correspondence: Dr Andrew E. Werchniak, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115, USA E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 30 January 2015
ª 2015 British Association of Dermatologists
thought to be most common in postmenopausal white women.5 EMPD rarely metastasizes, but when it does, the most commonly observed sites of metastasis are lymph nodes and bone, while metastases to other sites such as the liver have also been reported.6–8 Multiple therapies are available to treat EMPD, and risk stratification may help physicians determine how aggressively any individual patient should be treated. In this report, we summarize the prognostic factors for patients with EMPD (Table 1). The most important factors are depth of invasion and the presence or absence of extracutaneous involvement. The presence or absence of certain genetic tumour markers is also useful, but the current availability of this type of analysis is somewhat limited. The site of involvement and patient demographics appear to be less important.
Prognostic factors Depth of invasion
Depth of invasion has been repeatedly reported as an important prognosticator in EMPD, and has been
Clinical and Experimental Dermatology (2015) 40, pp473–478
473
Risk stratification in extramammary Paget disease J. M. Cohen et al.
Table 1 Prognostic factors in extramammary Paget disease. Factors
Important characteristics
References
Depth of invasion
Noninvasive (confined to epidermis): low risk Micro-invasive (into papillary dermis): intermediate risk Invasive (into reticular dermis): high risk < 1 mm: low risk ≥ 1 mm: high risk Lymph node or distant metastases beyond the skin: high risk
Crawford et al. (1999)11 Hatta et al. (2008)9 Ito et al. (2012)6 Karam and Dorigo (2012)10 Lam and Funaro (2010);2 Zhu et al. (2009)7 Aoyagi et al. (2008);8 Hata et al. (2014);12 Hatta et al. (2004);15 Hatta et al. (2008);9 Ito et al. (2012);6 Karam and Dorigo (2012);10 Lam and Funaro (2010);2 Moretto et al. (2013);14 Nakamura et al. (2012);16 Zhang et al. (2010);13 Zhu et al. (2009)7 Aoyagi et al. (2008)8
Extracutaneous involvement
Genetic profile
Site of lesion
CK7+, CK20 , GCDFP 15+: more likely primary EMPD (no underlying malignancy) CK7+, CK20+, GCDFP 15 : more likely malignancy-related Expression of Ki-67 and cyclin D1: high risk for metastasis Expression of MUC5AC: high risk for metastasis; loss of E-cadherin: high risk for metastasis Anorectal disease: increased mortality risk
Demographic features
Increased age: increased mortality risk
Hata et al. (2014)12 Hatta et al. (2008)9 Zhu et al. (2009)7 Karam and Dorigo (2012);10 Lam and Funaro (2010)2 Karam and Dorigo (2012)10
CK, cytokeratin; GCDFP, gross cystic disease fluid protein.
divided into three categories in the literature: noninvasive, micro-invasive and deeply invasive disease.6,7,9,10 Noninvasive (in situ) disease is confined to the epidermis (Fig. 1), while micro-invasive disease invades into the papillary dermis (Fig. 2) and deeply invasive disease involves the reticular dermis (Fig. 3). Increasing depth of invasion has consistently been found to increase disease-specific mortality. Some studies have found a statistically significant difference between survival with noninvasive and micro-invasive disease, while others have not.6,7,9,10 However, deeply invasive EMPD has been clearly shown to portend a poorer prognosis than noninvasive disease.2,6,7,9,10 One study of 21 cases of vulvar EMPD suggested that tumours that are < 1 mm thick are associated with a better prognosis than those > 1 mm, but more precise information regarding depth-specific prognostication is lacking.11
inguinal lymph node involvement has better outcomes than bilateral inguinal lymph node involvement, based on a small number of patients.9 It is clear that as the disease progresses from localized to regional and from regional to distant, the disease-specific survival decreases. Positron emission tomography–computed tomography (PET-CT) scans have been found to be useful in determining the extent of disease and detecting distant metastases, but have a low sensitivity for detecting microscopic metastases.7 Sentinel lymph node biopsy (SLNB) has been explored in small studies, and has been found to be a safe and effective way of screening for extracutaneous metastasis.14–16 The indications for SNLB remain unclear, but it is seems that individuals with clinical evidence of involved lymph nodes or disease affecting the dermis may benefit from SNLB.15,16 There is no evidence to suggest that SNLB is necessary in noninvasive disease.15,16
Extracutaneous involvement
Genetic and protein expression profile
Involvement of sites beyond the skin, either lymph nodes or distant metastases, is an important predictor of outcome.2,6,9,10,12,13 Both distant metastases and metastases to regional lymph nodes are associated with worse outcomes than disease localized to the skin.2,6,8–10 One study has suggested that ipsilateral
Increasingly, genetic characteristics of tumours have become important prognostic factors. One study found that several genes, including Her-2, p53 and bcl-2, are expressed in multiple different types of EMPD lesions.8 However, Ki-67 and cyclin D1 were found to be expressed more frequently in invasive lesions than in
474
Clinical and Experimental Dermatology (2015) 40, pp473–478
ª 2015 British Association of Dermatologists
Risk stratification in extramammary Paget disease J. M. Cohen et al.
(a)
(b)
Figure 1 (a) In situ/intraepidermal extramammary Paget disease of the vulva showing scattered cells with abundant pale cytoplasm (haematoxylin and eosin, original magnification 9 400). (b) Cytokeratin 7 immunostaining highlights the neoplastic cells but does not stain background epidermis (original magnification 9 400).
lesions that remained noninvasive.8 Moreover, lesions expressing both Ki-67 and cyclin D1 were more likely to be invasive than lesions expressing either Ki-67 or cyclin D1.8 Another study found that MUC5AC was more likely to be expressed in invasive and metastatic lesions than in noninvasive lesions.12 The carcinoembryonic antigen (CEA) level has been found to be higher in individuals with metastatic EMPD than in those with nonmetastatic EMPD. Additionally, the level of CEA seems to mirror disease progression, and can be a useful marker of clinical course.7,9 Finally, the loss of expression of E-cadherin is more common in metastatic than in nonmetastatic EMPD.7 Site of lesion
The overwhelming majority of EMPD cases present as genital (vulvar or penoscrotal) disease.2 However, data suggest that anorectal disease may be somewhat more aggressive than genital and perineal disease. One
ª 2015 British Association of Dermatologists
study showed that although this association did not exist in multivariate analysis, patients with anorectal EMPD had a statistically significantly decreased mean disease-specific survival compared with those without anorectal involvement.10 Patient demographics
Risk stratification based on demographics is difficult, given that many of the published studies on EMPD describe a small number of fairly homogeneous patients. However, one study utilized the Surveillance, Epidemiology and End Results (SEER) database to study a large number of patients with invasive EMPD.10 They found that there was no significant difference in disease-specific survival between men and women, but they did find that age was positively associated with mortality.10 This finding contrasts with the findings of previous studies, probably because those studies included a small number of patients. Racial differences have not been studied.
Clinical and Experimental Dermatology (2015) 40, pp473–478
475
Risk stratification in extramammary Paget disease J. M. Cohen et al.
Discussion Based on a synthesis of the existing EMPD literature, we discuss several important factors for the
Figure 2 Single nest of microinvasive carcinoma is visible, with
basal and parabasal layers of the epidermis present at the top of the photomicrograph (haematoxylin and eosin, 9 400).
(a)
prognosis of an individual with EMPD. Prognosis can be useful in both appropriate staging and selection of therapy for patients, and may also help in standardizing EMPD research. Overall, the strongest correlations with poor outcomes were related to depth of invasion and the presence or absence of metastases. Additionally, the genetic makeup of the tumour cells has been found to be an important indicator of outcome in some small studies. Weaker evidence exists to support a relationship between disease-specific survival and either the disease site or age of the patient. Based on these findings, patients with noninvasive (in situ) disease can be treated without SNLB or imaging. Patients with invasive disease should be considered for SNLB, particularly if there is invasion into the reticular dermis or beyond. PET scans should be reserved for those with a positive lymph node biopsy or with other symptoms or signs suggestive of more widespread involvement. While the factors discussed here are related to EMPD-specific survival, the presence of underlying malignancy is an important factor in management decisions. Data suggests that the presence of underlying malignancy does not change the risk of mortality from EMPD.6 However, individuals with systemic malignancy will require therapy for that malignancy in addition to therapy for EMPD. Individuals with EMPD, regardless of genotype, should undergo ageappropriate malignancy investigations, which may include colonoscopy; CT of the chest, abdomen and pelvis, cystoscopy; pelvic ultrasonography; Papanicolaou smear; colposcopy; and breast examination and mammography.2 (b)
Figure 3 (a) Deeply invasive extramammary Paget disease invading into the deep dermal collagen fibres (haematoxylin and eosin
9 400); (b) tumour cells highlighted by immunostaining for carcinoembryonic antigen (CEA) (original magnification 9 400).
476
Clinical and Experimental Dermatology (2015) 40, pp473–478
ª 2015 British Association of Dermatologists
Risk stratification in extramammary Paget disease J. M. Cohen et al.
We hope that this review succinctly summarizes some of the important prognostic factors in EMPD. The rarity of this disease makes it difficult to study. Some limitations to this study should be mentioned, including the small number of studies, the small sample sizes of relatively homogeneous patients, and that the search was restricted to publications that were in English and available through PubMed.
Conclusion Identification of risk factors that differentiate aggressive from indolent EMPD represents an important step in improving patient care and research. More data are needed to gain a better understanding of EMPD behaviour in a given clinical situation. Genetic tumour profiling represents a particularly promising area, and should be the focus of additional inquiry.
2
3
4
5
6
7
8
Learning points
9
• EMPD is an uncommon intraepithelial adeno-
carcinoma that can be indolent or quite aggressive. • Risk stratification in EMPD can be challenging. • The most important prognostic factors are depth of invasion and spread to extracutaneous sites. • Deeply invasive disease into the reticular dermis or depth of ≥ 1 mm have been found to indicate higher risk. • There is also a poorer prognosis associated with disease that has spread to extracutaneous sites, such as lymph nodes. • Tumour genetics, specifically expression of Ki-67, cyclin D1 and MUC5AC and loss of E-cadherin, have been shown to increase risk of extracutaneous spread, and may represent an important emerging factor. • There is less evidence supporting the importance of age and site of lesion in risk stratification of EMPD.
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review of the literature emphasizing management. Dermatol Surg 2013; 39: 69–75. Lam C, Funaro D. Extramammary Paget’s disease: summary of current knowledge. Dermatol Clin 2010; 28: 807–26. Vincent J, Taube JM. Pigmented extramammary Paget disease of the abdomen: a potential mimicker of melanoma. Dermatol Online J 2011; 17: 13. Chanda JJ. Extramammary Paget’s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13: 1009–14. Wang X, Yang W, Yang J. Extramammary Paget’s disease with the appearance of a nodule: a case report. BMC Cancer 2010; 10: 405. Ito Y, Igawa S, Ohishi Y et al. Prognostic indicators in 35 patients with extramammary Paget’s disease. Dermatol Surg 2012; 38: 1938–44. Zhu Y, Ye DW, Yao XD et al. Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget’s disease. Br J Dermatol 2009; 161: 577–82. Aoyagi S, Akiyama M, Shimizu H. High expression of Ki67 and cyclin D1 in invasive extramammary Paget’s disease. J Dermatol Sci 2008; 50: 177–84. Hatta N, Yamada M, Hirano T et al. Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 2008; 158: 313–18. Karam A, Dorigo O. Treatment outcomes in a large cohort of patients with invasive Extramammary Paget’s disease. Gynecol Oncol 2012; 125: 346–51. Crawford D, Nimmo M, Clement PB et al. Prognostic factors in Paget’s disease of the vulva: a study of 21 cases. Int J Gynecol Pathol 1999; 18: 351–9. Hata H, Abe R, Hoshina D et al. MUC5AC expression correlates with invasiveness and progression of extramammary Paget’s disease. J Eur Acad Dermatol Venereol 2014; 28: 727–32. Zhang N, Gong K, Zhang X et al. Extramammary Paget’s disease of scrotum–report of 25 cases and literature review. Urol Oncol 2010; 28: 28–33. Moretto P, Nair VJ, Hallani SE et al. Management of penoscrotal extramammary Paget disease: case series and review of the literature. Curr Oncol 2013; 20: e311–20. Hatta N, Morita R, Yamada M et al. Sentinel lymph node biopsy in patients with extramammary Paget’s disease. Dermatol Surg 2004; 30: 1329–34. Nakamura Y, Fujisawa Y, Ishikawa M et al. Usefulness of sentinel lymph node biopsy for extramammary Paget disease. Br J Dermatol 2012; 167: 954–6.
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CPD questions Learning objective To gain an understanding of the prognostic factors in extramammary Paget disease. Question 1
Extramammary Paget disease of the genitals is associated with which of the following types of internal malignancy? a) Haematological. b) Genitourinary tract. c) Upper gastrointestinal tract. d) Lower gastrointestinal tract. e) Melanoma. Question 2
A poor prognosis is associated with a depth of invasion greater than or equal to which of the following? a) 0.1 mm. b) 0.5 mm. c) 0.75 mm. d) 1.0 mm. e) 1.25 mm.
Question 3
Expression of Cyclin D1 is useful for predicting the presence of which of the following? a) Genital disease. b) Associated genitourinary malignancy. c) Invasive disease. d) Associated gastrointestinal malignancy. e) Noninvasive disease.
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Question 4
Expression of MUC5AC is useful for predicting which of the following? a) Invasive and metastatic potential. b) Associated internal malignancy. c) Anal involvement. d) Tumour restricted to the papillary dermis. e) Rapid disease progression. Question 5
What is the role for positron emission tomography (PET) scans in extramammary Paget disease (EMPD)? a) There is never a role for PET Scans in EMPD. b) For detecting microscopic metastases. c) For determining extent of distant metastases. d) Only in anal EMPD. e) PET scans should be done in all patients with EMPD. Instructions for answering questions
This learning activity is freely available online at http://www.wileyhealthlearning.com/ced. Users are encouraged to • Read the article in print or online, paying particular attention to the learning points and any author conflict of interest disclosures • Reflect on the article • Register or login online at www.wileyhealthlearning.com/ced and answer the CPD questions • Complete the required evaluation component of the activity Once the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self-certified entry. This activity will be available for CPD credit for 2 years following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional period.
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