- Email: [email protected]
Clinical Presentation of Extramammary Paget Disease of the Axilla in a Male Patient
Case Report
Clinical Presentation of Extramammary Paget Disease of the Axilla in a Male Patient Michael Deutsch,1 Janet Yeh,1 Dianne Grunes,2 Elizabeth Horowitz,1 Elaheh Johnson,1 Kathie-Ann Joseph1 Clinical Practice Points Extramammary Paget disease is a rare condition most
Immunohistochemical staining for markers including
often found in the penile and vulvar regions but is not necessarily limited to these locations. The nonspecific symptoms and visual presentation can mimic a variety of other dermatological conditions, often delaying diagnosis.
cytokeratin 7 are becoming increasingly important in making the diagnosis. The current mainstay of therapy is surgical excision with wide margins. Multiple new modalities are being tested to reduce the need for operative definitive therapy, potentially reducing morbidity.
Clinical Breast Cancer, Vol. 15, No. 2, e159-61 ª 2015 Elsevier Inc. All rights reserved. Keywords: Cytokeratin 7, Immunohistochemical staining of punch biopsy, Mohs micrographic surgery
Introduction Extramammary Paget disease (EMPD) is an infrequently occurring type of intraepithelial adenocarcinoma that does not include the breast tissue. Apocrine gland-bearing areas are the most frequently affected sites, which include the vulva, scrotum, penis, axilla, and even the eyelid.1 There are only a limited number of isolated cases of Paget disease of the axilla in the literature.
Case Report The patient was a 65-year-old man who presented with complaints of an axillary mass that had been increasing in size. His medical and surgical history included significant hearing loss and bilateral cataract surgery. He had no history of tobacco or alcohol use. He was seen at another institution in 2009, where the axillary mass was worked up with a skin biopsy, mammogram, and ultrasound. As per the patient, he was told the lesion was noncancerous and given a topical ointment. Since then, the lesion had increased in size and was noted to bleed on occasion. He has not noted any other
1
Department of Surgery Department of Pathology Bellevue Medical Center, New York University School of Medicine, New York, NY 2
breast masses, skin lesions, or changes to the nipple. He denied any pruritic symptoms. He denied any other systemic symptoms, including weight loss, bone pain, headache, fever, or chills. On obtaining the reports from 2009, we found that the pathology from the skin biopsy was consistent with Paget disease. The mammogram showed fibroglandular tissue density in the retroareolar region of both breasts, compatible with bilateral gynecomastia. There were no suspicious foci or mammography evidence of malignancy. The ultrasound also did not identify any solid masses or abnormalappearing lymph nodes. On general physical examination the left axilla was remarkable for a superficial 8 6-cm whitish raised cauliflower type lesion with well demarcated borders (Figure 1). There was no underlying adenopathy. The bilateral breasts were without discrete masses, no nipple or areolar lesions noted, and the nipples were everted. A punch biopsy was obtained at our institution and pathology from the lesion showed Paget disease involving acantholytic epidermis with verrucous hyperplasia (Figures 2 and 3). The tumor cells were positive for staining with anti-cytokeratin 8/18 (CAM 5.2), cytokeratin 7 (CK7), and carcinoembryonic antigen (CEA). They were was negative for S-100, CK20, and thyroid transcription factor-1. The patient was referred to surgical oncology for excision.
Submitted: Sep 22, 2014; Accepted: Oct 15, 2014; Epub: Oct 22, 2014 Address for correspondence: Kathie-Ann Joseph, MD, MPH, Breast Services, South Manhattan Network, NYC Health and Hospitals Corporation, NYU Langone Medical Center, 550 First Ave, NBV-15S6, New York, NY 10016 Fax: 212-263-8640; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.10.004
Discussion Paget disease of the breast is a malignant condition of the skin accounting for somewhere between 1% and 4% of all breast cancers.2 EMPD is an equally rare subtype, with only a few hundred
Clinical Breast Cancer April 2015
- e159
Clinical Presentation of Extramammary Paget Disease Figure 1 On General Physical Examination the Left Axilla Is Remarkable for a Superficial 8 3 6-cm Whitish Raised Cauliflower Type Lesion With Well Demarcated Borders
cases reported in world literature.3,4 When it occurs, it is often found in or around the reproductive organs—namely the penis and vulva—although reports of axillary and other sites have occurred.1,5 It is also important to note that unlike mammary Paget disease, which is more likely to have an underlying malignancy, cases of EMPD are less likely to find an underlying pathology as in this patient’s case.6 Women are affected more commonly than men with a ratio approaching 4:1 of female-to-male.7 The average age at presentation is approximately 75 years.8,9 Clinically, the presentation of EMPD is nonspecific and can mimic a variety of other dermatological conditions. A brief list of
Figure 2 Pathology From the Lesion Showed Paget Disease Involving Acantholytic Epidermis With Verrucous Hyperplasia (4X magnification)
Figure 3 Pathology From the Lesion Showed Paget Disease Involving Acantholytic Epidermis With Verrucous Hyperplasia (10X magnification)
possible differentials includes Bowen disease, various tinea infections, psoriasis, and eczema.10 Symptoms are equally nonspecific with patients experiencing anything from itching, burning, and pain, to being completely asymptomatic. As a result, delays in diagnosis are common. Although a high degree of insight is required to make the diagnosis, a few histological markers are useful to confirm it. Diagnosis is made using immunohistochemical analysis along with punch biopsy. Standard hematoxylin and eosin staining shows the presence of large cells with a bluish-tinted cytoplasm, called Paget cells.4,11 Additionally, positive immunohistochemical staining for CK7 is one marker that has been identified to help confirm the diagnosis. In one immunohistochemical review of some 80 total mammary and EMPD cases, all the EMPD cases stained positive for CK8/18 and CK7,12 and higher CKs were negative. Other markers including CAM 5.2 and CEA are also useful in differentiating this entity from Bowen disease.5 These observations were confirmed in our case report. Recently, Paget disease, particularly that of the vulva, has been classified into 2 broad groups by Wilkinson and Brown.13 However, further work remains to be done on this classification scheme to be useful in deciding the best treatment modality. Currently, the mainstay of therapy involves surgery with wide local excision. Techniques like Mohs micrographic surgery have become increasing popular because of the ability to completely evaluate the margins without significant tissue loss. Despite this, failure rates with recurrence are common. A literature review shows recurrence ranging from as low as 15% up to 60%, depending on the size of margins.5,14,15 New therapies are also emerging to help with treatment. Topical imiquimod and 5-fluoruracil have been used offlabel with some success.16 Other treatments, including systemic chemotherapy, radiation therapy, and lasers, are also being studied. Regardless, overall prognosis is good and survival rates are high if disease is limited and clear margins are achieved without the presence of metastasis.17
Conclusion
e160
-
Extramammary Paget disease is an infrequently occurring type of intraepithelial adenocarcinoma of which there are only several hundred cases in the literature. Careful clinical examination,
Clinical Breast Cancer April 2015
Michael Deutsch et al immunohistochemical workup, and staging are necessary to accurately differentiate EMPD from other closely related skin malignancies that mimic it. In our patient, its unusual location and presentation was an unexpected finding and possibly was thought to be an eczematoid like disease; hence, topical ointment was prescribed. Additionally, other red herrings included that the patient was a Haitian man with a disease most commonly associated with postmenopausal Caucasian women. Additionally, he was also younger than the typical age group for this condition. However, further review of punch biopsy reports and important staining for CKs, CEA, and S-100 among others helped confirm that the pathology was consistent with EMPD. Fortunately, despite delays in time to definitive treatment, overall prognosis remains good and survival high with wide surgical margin resection.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Whorton CM, Patterson JB. Carcinoma of Moll glands with extramammary Paget disease of the eyelid. Cancer 1955; 8:1009-15. 2. Dalberg K, Hellborg H, Warnberg F. Paget disease of the nipple in a populationbased cohort. Breast Cancer Res Treat 2008; 111:313-9.
3. Kanitakis J. Mammary and extramammary Paget disease. J Eur Acad Dermatol Venereol 2007; 21:581-90. 4. Shepherd V, Davidson EJ, Davies-Humphreys J. Extramammary Paget disease. BJOG 2005; 112:273-9. 5. Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget disease. Br J Dermatol 2000; 142:59-65. 6. Lloyd J, Flanagan AM. Mammary and extramammary Paget disease. J Clin Pathol 2000; 53:742-9. 7. Chanda JJ. Extramammary Paget disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13:1009-14. 8. Ito Y, Igawa S, Ohishi Y, et al. Prognostic indicators in 35 patients with extramammary Paget disease. Dermatol Surg 2012; 38:1938-44. 9. Pang J, Assaad D, Breen D, et al. Extramammary Paget disease: review of patients seen in a non-melanoma skin cancer clinic. Curr Oncol 2010; 17:43-5. 10. Ekwueme KC, Zakhour HD, Parr NJ. Extramammary Paget disease of the penis: a case report and review of the literature. J Med Case Rep 2009; 3:4. 11. Smith KJ, Tuur S, Corvette D, et al. Cytokeratin 7 staining in mammary and extramammary Paget disease. Mod Pathol 1997; 10:1069-74. 12. Liegl B, Leibl S, Gogg-Kamerer M, et al. Mammary and extramammary Paget disease: an immunohistochemical study of 83 cases. Histopathology 2007; 50: 439-47. 13. Wilkinson EJ, Brown HM. Vulvar Paget disease of urothelial origin: a report of three cases and a proposed classification of vulvar Paget disease. Hum Pathol 2002; 33:549-54. 14. Chiu TW, Wong PS, Ahmed K, et al. Extramammary Paget disease in Chinese males: a 21-year experience. World J Surg 2007; 31:1941-6. 15. Kitajima S, Yamamoto K, Tsuji T, et al. Triple extramammary Paget disease. Dermatol Surg 1997; 23:1035-8. 16. Housel JP, Izikson L, Zeitouni NC. Noninvasive extramammary Paget disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute. Dermatol Surg 2010; 36:1718-24. 17. Zhu Y, Ye DW, Chen ZW, et al. Frozen section-guided wide local excision in the treatment of penoscrotal extramammary Paget’s disease. BJU Int 2007; 100: 1282-7.
Clinical Breast Cancer April 2015
- e161
Clinical Presentation of Extramammary Paget Disease of the Axilla in a Male Patient Michael Deutsch,1 Janet Yeh,1 Dianne Grunes,2 Elizabeth Horowitz,1 Elaheh Johnson,1 Kathie-Ann Joseph1 Clinical Practice Points Extramammary Paget disease is a rare condition most
Immunohistochemical staining for markers including
often found in the penile and vulvar regions but is not necessarily limited to these locations. The nonspecific symptoms and visual presentation can mimic a variety of other dermatological conditions, often delaying diagnosis.
cytokeratin 7 are becoming increasingly important in making the diagnosis. The current mainstay of therapy is surgical excision with wide margins. Multiple new modalities are being tested to reduce the need for operative definitive therapy, potentially reducing morbidity.
Clinical Breast Cancer, Vol. 15, No. 2, e159-61 ª 2015 Elsevier Inc. All rights reserved. Keywords: Cytokeratin 7, Immunohistochemical staining of punch biopsy, Mohs micrographic surgery
Introduction Extramammary Paget disease (EMPD) is an infrequently occurring type of intraepithelial adenocarcinoma that does not include the breast tissue. Apocrine gland-bearing areas are the most frequently affected sites, which include the vulva, scrotum, penis, axilla, and even the eyelid.1 There are only a limited number of isolated cases of Paget disease of the axilla in the literature.
Case Report The patient was a 65-year-old man who presented with complaints of an axillary mass that had been increasing in size. His medical and surgical history included significant hearing loss and bilateral cataract surgery. He had no history of tobacco or alcohol use. He was seen at another institution in 2009, where the axillary mass was worked up with a skin biopsy, mammogram, and ultrasound. As per the patient, he was told the lesion was noncancerous and given a topical ointment. Since then, the lesion had increased in size and was noted to bleed on occasion. He has not noted any other
1
Department of Surgery Department of Pathology Bellevue Medical Center, New York University School of Medicine, New York, NY 2
breast masses, skin lesions, or changes to the nipple. He denied any pruritic symptoms. He denied any other systemic symptoms, including weight loss, bone pain, headache, fever, or chills. On obtaining the reports from 2009, we found that the pathology from the skin biopsy was consistent with Paget disease. The mammogram showed fibroglandular tissue density in the retroareolar region of both breasts, compatible with bilateral gynecomastia. There were no suspicious foci or mammography evidence of malignancy. The ultrasound also did not identify any solid masses or abnormalappearing lymph nodes. On general physical examination the left axilla was remarkable for a superficial 8 6-cm whitish raised cauliflower type lesion with well demarcated borders (Figure 1). There was no underlying adenopathy. The bilateral breasts were without discrete masses, no nipple or areolar lesions noted, and the nipples were everted. A punch biopsy was obtained at our institution and pathology from the lesion showed Paget disease involving acantholytic epidermis with verrucous hyperplasia (Figures 2 and 3). The tumor cells were positive for staining with anti-cytokeratin 8/18 (CAM 5.2), cytokeratin 7 (CK7), and carcinoembryonic antigen (CEA). They were was negative for S-100, CK20, and thyroid transcription factor-1. The patient was referred to surgical oncology for excision.
Submitted: Sep 22, 2014; Accepted: Oct 15, 2014; Epub: Oct 22, 2014 Address for correspondence: Kathie-Ann Joseph, MD, MPH, Breast Services, South Manhattan Network, NYC Health and Hospitals Corporation, NYU Langone Medical Center, 550 First Ave, NBV-15S6, New York, NY 10016 Fax: 212-263-8640; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.10.004
Discussion Paget disease of the breast is a malignant condition of the skin accounting for somewhere between 1% and 4% of all breast cancers.2 EMPD is an equally rare subtype, with only a few hundred
Clinical Breast Cancer April 2015
- e159
Clinical Presentation of Extramammary Paget Disease Figure 1 On General Physical Examination the Left Axilla Is Remarkable for a Superficial 8 3 6-cm Whitish Raised Cauliflower Type Lesion With Well Demarcated Borders
cases reported in world literature.3,4 When it occurs, it is often found in or around the reproductive organs—namely the penis and vulva—although reports of axillary and other sites have occurred.1,5 It is also important to note that unlike mammary Paget disease, which is more likely to have an underlying malignancy, cases of EMPD are less likely to find an underlying pathology as in this patient’s case.6 Women are affected more commonly than men with a ratio approaching 4:1 of female-to-male.7 The average age at presentation is approximately 75 years.8,9 Clinically, the presentation of EMPD is nonspecific and can mimic a variety of other dermatological conditions. A brief list of
Figure 2 Pathology From the Lesion Showed Paget Disease Involving Acantholytic Epidermis With Verrucous Hyperplasia (4X magnification)
Figure 3 Pathology From the Lesion Showed Paget Disease Involving Acantholytic Epidermis With Verrucous Hyperplasia (10X magnification)
possible differentials includes Bowen disease, various tinea infections, psoriasis, and eczema.10 Symptoms are equally nonspecific with patients experiencing anything from itching, burning, and pain, to being completely asymptomatic. As a result, delays in diagnosis are common. Although a high degree of insight is required to make the diagnosis, a few histological markers are useful to confirm it. Diagnosis is made using immunohistochemical analysis along with punch biopsy. Standard hematoxylin and eosin staining shows the presence of large cells with a bluish-tinted cytoplasm, called Paget cells.4,11 Additionally, positive immunohistochemical staining for CK7 is one marker that has been identified to help confirm the diagnosis. In one immunohistochemical review of some 80 total mammary and EMPD cases, all the EMPD cases stained positive for CK8/18 and CK7,12 and higher CKs were negative. Other markers including CAM 5.2 and CEA are also useful in differentiating this entity from Bowen disease.5 These observations were confirmed in our case report. Recently, Paget disease, particularly that of the vulva, has been classified into 2 broad groups by Wilkinson and Brown.13 However, further work remains to be done on this classification scheme to be useful in deciding the best treatment modality. Currently, the mainstay of therapy involves surgery with wide local excision. Techniques like Mohs micrographic surgery have become increasing popular because of the ability to completely evaluate the margins without significant tissue loss. Despite this, failure rates with recurrence are common. A literature review shows recurrence ranging from as low as 15% up to 60%, depending on the size of margins.5,14,15 New therapies are also emerging to help with treatment. Topical imiquimod and 5-fluoruracil have been used offlabel with some success.16 Other treatments, including systemic chemotherapy, radiation therapy, and lasers, are also being studied. Regardless, overall prognosis is good and survival rates are high if disease is limited and clear margins are achieved without the presence of metastasis.17
Conclusion
e160
-
Extramammary Paget disease is an infrequently occurring type of intraepithelial adenocarcinoma of which there are only several hundred cases in the literature. Careful clinical examination,
Clinical Breast Cancer April 2015
Michael Deutsch et al immunohistochemical workup, and staging are necessary to accurately differentiate EMPD from other closely related skin malignancies that mimic it. In our patient, its unusual location and presentation was an unexpected finding and possibly was thought to be an eczematoid like disease; hence, topical ointment was prescribed. Additionally, other red herrings included that the patient was a Haitian man with a disease most commonly associated with postmenopausal Caucasian women. Additionally, he was also younger than the typical age group for this condition. However, further review of punch biopsy reports and important staining for CKs, CEA, and S-100 among others helped confirm that the pathology was consistent with EMPD. Fortunately, despite delays in time to definitive treatment, overall prognosis remains good and survival high with wide surgical margin resection.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Whorton CM, Patterson JB. Carcinoma of Moll glands with extramammary Paget disease of the eyelid. Cancer 1955; 8:1009-15. 2. Dalberg K, Hellborg H, Warnberg F. Paget disease of the nipple in a populationbased cohort. Breast Cancer Res Treat 2008; 111:313-9.
3. Kanitakis J. Mammary and extramammary Paget disease. J Eur Acad Dermatol Venereol 2007; 21:581-90. 4. Shepherd V, Davidson EJ, Davies-Humphreys J. Extramammary Paget disease. BJOG 2005; 112:273-9. 5. Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget disease. Br J Dermatol 2000; 142:59-65. 6. Lloyd J, Flanagan AM. Mammary and extramammary Paget disease. J Clin Pathol 2000; 53:742-9. 7. Chanda JJ. Extramammary Paget disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13:1009-14. 8. Ito Y, Igawa S, Ohishi Y, et al. Prognostic indicators in 35 patients with extramammary Paget disease. Dermatol Surg 2012; 38:1938-44. 9. Pang J, Assaad D, Breen D, et al. Extramammary Paget disease: review of patients seen in a non-melanoma skin cancer clinic. Curr Oncol 2010; 17:43-5. 10. Ekwueme KC, Zakhour HD, Parr NJ. Extramammary Paget disease of the penis: a case report and review of the literature. J Med Case Rep 2009; 3:4. 11. Smith KJ, Tuur S, Corvette D, et al. Cytokeratin 7 staining in mammary and extramammary Paget disease. Mod Pathol 1997; 10:1069-74. 12. Liegl B, Leibl S, Gogg-Kamerer M, et al. Mammary and extramammary Paget disease: an immunohistochemical study of 83 cases. Histopathology 2007; 50: 439-47. 13. Wilkinson EJ, Brown HM. Vulvar Paget disease of urothelial origin: a report of three cases and a proposed classification of vulvar Paget disease. Hum Pathol 2002; 33:549-54. 14. Chiu TW, Wong PS, Ahmed K, et al. Extramammary Paget disease in Chinese males: a 21-year experience. World J Surg 2007; 31:1941-6. 15. Kitajima S, Yamamoto K, Tsuji T, et al. Triple extramammary Paget disease. Dermatol Surg 1997; 23:1035-8. 16. Housel JP, Izikson L, Zeitouni NC. Noninvasive extramammary Paget disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute. Dermatol Surg 2010; 36:1718-24. 17. Zhu Y, Ye DW, Chen ZW, et al. Frozen section-guided wide local excision in the treatment of penoscrotal extramammary Paget’s disease. BJU Int 2007; 100: 1282-7.
Clinical Breast Cancer April 2015
- e161