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Extramammary Paget disease of the perianal region: the potential role of imiquimod in achieving disease control

Extramammary Paget disease of the perianal region: the potential role of imiquimod in achieving... Extramammary Paget disease (EMPD) is a rare perineal neoplasia associated with a high rate of local recurrence. Surgical excision is the standard treatment; however, this has high rates of post-operative morbidity in combination with potentially mutilating results. Previous literature has demonstrated good response with imiquimod 5% cream in patients with vulval EMPD, yet its effectiveness in primary perianal disease is unknown. We describe the case of a 40-year-old woman presenting with EMPD of the perianal region, providing detailed histological and pictoral evidence of its response to topical imiquimod 5% cream over a 16-week period, which initially resulted in remission prior to metastatic lymph node recurrence. This case demonstrates the potential for topical imiquimod cream to avoid major sur- gery and its associated complications in patients presenting with EMPD of the perianal region. We discuss the current evidence for treating this rare condition with medical therapy, how this case adds to current literature and possible future directions. INTRODUCTION There are several treatment modalities described in the Extramammary Paget disease (EMPD) is similar histologically to management of EMPD including surgery, chemotherapy and Paget disease of the breast and predominantly affects external irradiation with variable curative rates. However, relapse can genitalia. It is a rare malignancy and primary cutaneous disease occur in >30% of patients [5]. Surgery is the first-line treatment; usually involves the vulva [1]. Secondary EMPD disease is defined however, surgical margins are frequently positive, resulting in as a neoplasia of a non-cutaneous tissue [2], the associated high recurrence rates after surgery [6]. malignancy is frequently anal and/or rectal adenocarcinoma Imiquimod (Aldara , 3 M Health Care Limited) is an immune with involvement of the anogenital skin [3]. Histologically, stimulator that is highly effective in the treatment of vulval primary or cutaneous EMPD is defined as a non-invasive intra- intra-epithelial neoplasia [7]. Growing evidence is beginning to epidermal adenocarcinoma that can spread into neighbouring suggest a role for imiquimod 5% cream in EMPD, particularly epithelial glandular appendices [4]. EMPD of vulval origin [5], in achieving disease-control or Received: May 1, 2016. Accepted: May 24, 2016 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2016. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1 2 S.R. Knight et al. complete response. However, limited evidence exists for the inflammation of the right buttock but no evidence of disease treatment of primary EMPD of the perianal region with spread beyond the perianal skin. imiquimod. Due to her elevated BMI and the perianal location of her In this case report, we present a female patient of 40 years EMPD, it was felt that the standard option of surgical resection old with perianal EMPD, treated with imiquimod 5% cream. by performing Mohs micrographic surgery or wide local excision would be associated with a high risk of perioperative morbidity. The potential for local control in a disease with a well-described CASE REPORT pattern for local recurrence, while avoiding potentially disfigur- A 40-year-old woman presented to the Dermatology outpatient ing surgery, was felt to be a viable alternative option. clinic with a 2-year history of a painful rash in the perianal A trial of imiquimod cream (5%) was commenced with a region associated with pruritus and erythema. The patient regimen of one application each night for 5 days together with denied any bowel or gynaecological symptoms. Her medical 2 rest days per week. The rest period was used to allow time history included erythema nodosum, polycystic ovary disease for any skin inflammation caused by imiquimod to settle. and a body mass index (BMI) >30. Analgesia (Paracetamol, Diclofenac and Tramadol) was pre- On examination, an erythematous perianal lesion was present scribed to provide pain relief for potential local skin reactions. with associated superficial excoriation (Fig. 1). An initial punch On review at the first 2 weeks of treatment, the patient had tol- biopsy was taken (Fig. 2A), which demonstrated a unilateral erated the imiquimod 5% cream, with only two applications well-demarcated eroded lesion. Immunohistochemical staining missed due to vomiting secondary to a viral infection. (Fig. 2B) showed malignant cells in the epidermis, staining posi- By Week 5, the area of erythema had visibly reduced, with a tively for CK7 and EMA. The tissue stained negative for CK20 and 1-cm rim of granulation tissue around its edge (Fig. 1B). The oestrogen receptors. A diagnosis of EMPD was given. patient’s progress was reviewed at 12 and 16 weeks, with a Breast and gynaecological examinations of the patient were stepwise regression of the EMPD identified. At 16-week examin- normal, while a colonoscopy did not identify any evidence of ation demonstrated almost complete resolution of the perianal extramammary bowel disease. A computed tomography (CT) erythema (Fig. 1C). Further multiple, random punch biopsies of chest, abdomen and pelvis demonstrated subcutaneous the perianal skin were taken 1 month later, which demon- strated variable evidence of chronic inflammation with epider- mal reaction (Fig. 2C), but no residual EMPD. A follow-up MRI of the pelvis 16 weeks after the discontinu- ation of treatment showed residual thickening consistent with inflammation at the site of previous subcutaneous nodules. A CT chest, abdomen and pelvis did not identify any distal EMPD deposits. The patient remained in remission for 18 months, however inguinal lymphadenopathy was noted at this time and a biopsy demonstrated adenocarcinoma suggesting malignant trans- formation of her EMPD. DISCUSSION We describe the primary local treatment of perianal EMPD with imiquimod 5% cream over a 16-week period initially resulting in remission prior to lymph node spread at 18 months. This provides further evidence, both in disease response and opti- Figure 1: (A) Initial presentation with an erythematous perianal lesion with mal treatment time, which imiquimod might potentially be associated superficial excoriation. (B) Appearance of rash following 5 weeks and considered as a first-line treatment for perineal EMPD. (C) 16 weeks of treatment with 5% imiquimod cream, demonstrating stepwise Imiquimod induces the immune response by activating improvement. (D) Appearance of perineum at 6-month follow-up following completion of treatment. macrophages and other inflammatory cells by increasing syn- thesis of pro-inflammatory cytokines while also producing distinctive apoptosis in epithelial cells [7]. A retrospective case- series of 23 patients demonstrated up to 80% clinical response with imiquimod for EMPD of the vulva [2]. The clinical response appears to be related to duration of imiquimod therapy in weeks [2]; however, the optimal length of treatment time remains to be defined. Surgical resection of perianal EMPD is an invasive procedure associated with a high perioperative morbidity. Furthermore, the potential of disfiguring surgery and permanent stoma for- mation may have a profound psychological impact on the patient. Recurrence rates could approach up to 50% despite Figure 2: (A) Initial punch biopsy of the perianal lesion demonstrated a well- adequate surgical resection margins [8]. demarcated erosive lesion with associated fibrin deposition and acute inflam- Close monitoring of patients during the treatment period is mation. (B) Following the 16-week course of imiquimod cream, repeat biopsies particularly important, both to monitor response of EMPD to demonstrated chronic inflammation with epidermal reaction and prominent treatment and the side-effect profile experienced by patients vascular proliferation, but no evidence of EMPD. Both produced with haema- toxylin & eosin staining. Scale bar 500 μm (A) and 200 μm (B). secondary to topical imiquimod. Following the completion of Extramammary Paget disease of the perianal region 3 imiquimod treatment, biopsies are mandatory in order to including gross cystic disease fluid protein-15 and cytokeratin assess residual disease, as recurrence is common. Longer term 20 expression. Arch Pathol Lab Med 1998;122:1077–81. data regarding recurrence following topical therapy, and 2. Luyten A, Sörgel P, Clad A, Gieseking F, Maass-Poppenhusen K, adequacy of subsequent surgical resection is awaited [6]. In this Lellé RJ, et al. Treatment of extramammary Paget disease of case recurrence was noted by palpable inguinal lymph nodes, the vulva with imiquimod: a retrospective, multicentre study with no skin or colonic lesion found. This highlights the by the German Colposcopy Network. JAm AcadDermatol importance of regular follow-up in perineal EMPD, with a high 2014;70:644–50. clinical index of suspicion for relapse or malignant change. 3. Goldblum JR, Hart WR. Perianal Paget’s disease: a histologic Developing an evidence-base for the use of imiquimod, as and immunohistochemical study of 19 cases. Am J Surg either first-line therapy or for disease recurrence, will be limited Pathol 1997;21:1178–87. by the potential number of new EMPD cases. An international 4. Wilkinson EJ, Brown HM. Vulvar Paget disease of urothelial register [9] to collate data on each patient case should be consid- origin: a report of three cases and a proposed classification ered to determine the optimal length of imiquimod treatment, of vulvar Paget disease. Hum Pathol 2002;33:549–54. together with the long-term follow-up of patients following 5. Luyten A, Brummer O, Kühnle H, Reinecke-Lüthge A, Petry treatment. In addition, it may also aid the identification of KU. New options for the treatment of Pagets disease of the patient cohorts most likely to respond to imiquimod therapy. vulva. Geburtshilfe Frauenheilkd 2006;66:1081–6. 6. Shaco-Levy R, Bean SM, Vollmer RT, Jewell E, Jones EL, Valdes CL, et al. Paget disease of the vulva: a study of CONFLICT OF INTEREST STATEMENT 56 cases. Eur J Obstet Gynecol Reprod Biol 2010;149:86–91. None declared. 7. Schon MP, Wienrich BG, Drewnlok C, Bong AB, Eberle J, Geilen CC, et al. Death receptor-independent apoptosis in PATIENT CONSENT malignant melanoma induced by the small-molecule immune response modifier imiquimod. J Invest Dermatol Written consent was gained from the patient prior to article 2004;122:1266–76. submission. 8. Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s disease. Br J Dermatol REFERENCES 2000;142:59–65. 9. Genetic and Rare Diseases Information Centre. http:// 1. Novak MA, Guerriere-Kovach P, Pathan A, Campbell TE, rarediseases.info.nih.gov/gard (22 April 2015, date last Deppisch LM. Perianal Paget’s disease: distinguishing primary accessed). and secondary lesions using immunohistological studies http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Surgical Case Reports Oxford University Press

Extramammary Paget disease of the perianal region: the potential role of imiquimod in achieving disease control

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Oxford University Press
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Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2016.
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2042-8812
DOI
10.1093/jscr/rjw110
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Abstract

Extramammary Paget disease (EMPD) is a rare perineal neoplasia associated with a high rate of local recurrence. Surgical excision is the standard treatment; however, this has high rates of post-operative morbidity in combination with potentially mutilating results. Previous literature has demonstrated good response with imiquimod 5% cream in patients with vulval EMPD, yet its effectiveness in primary perianal disease is unknown. We describe the case of a 40-year-old woman presenting with EMPD of the perianal region, providing detailed histological and pictoral evidence of its response to topical imiquimod 5% cream over a 16-week period, which initially resulted in remission prior to metastatic lymph node recurrence. This case demonstrates the potential for topical imiquimod cream to avoid major sur- gery and its associated complications in patients presenting with EMPD of the perianal region. We discuss the current evidence for treating this rare condition with medical therapy, how this case adds to current literature and possible future directions. INTRODUCTION There are several treatment modalities described in the Extramammary Paget disease (EMPD) is similar histologically to management of EMPD including surgery, chemotherapy and Paget disease of the breast and predominantly affects external irradiation with variable curative rates. However, relapse can genitalia. It is a rare malignancy and primary cutaneous disease occur in >30% of patients [5]. Surgery is the first-line treatment; usually involves the vulva [1]. Secondary EMPD disease is defined however, surgical margins are frequently positive, resulting in as a neoplasia of a non-cutaneous tissue [2], the associated high recurrence rates after surgery [6]. malignancy is frequently anal and/or rectal adenocarcinoma Imiquimod (Aldara , 3 M Health Care Limited) is an immune with involvement of the anogenital skin [3]. Histologically, stimulator that is highly effective in the treatment of vulval primary or cutaneous EMPD is defined as a non-invasive intra- intra-epithelial neoplasia [7]. Growing evidence is beginning to epidermal adenocarcinoma that can spread into neighbouring suggest a role for imiquimod 5% cream in EMPD, particularly epithelial glandular appendices [4]. EMPD of vulval origin [5], in achieving disease-control or Received: May 1, 2016. Accepted: May 24, 2016 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 2016. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1 2 S.R. Knight et al. complete response. However, limited evidence exists for the inflammation of the right buttock but no evidence of disease treatment of primary EMPD of the perianal region with spread beyond the perianal skin. imiquimod. Due to her elevated BMI and the perianal location of her In this case report, we present a female patient of 40 years EMPD, it was felt that the standard option of surgical resection old with perianal EMPD, treated with imiquimod 5% cream. by performing Mohs micrographic surgery or wide local excision would be associated with a high risk of perioperative morbidity. The potential for local control in a disease with a well-described CASE REPORT pattern for local recurrence, while avoiding potentially disfigur- A 40-year-old woman presented to the Dermatology outpatient ing surgery, was felt to be a viable alternative option. clinic with a 2-year history of a painful rash in the perianal A trial of imiquimod cream (5%) was commenced with a region associated with pruritus and erythema. The patient regimen of one application each night for 5 days together with denied any bowel or gynaecological symptoms. Her medical 2 rest days per week. The rest period was used to allow time history included erythema nodosum, polycystic ovary disease for any skin inflammation caused by imiquimod to settle. and a body mass index (BMI) >30. Analgesia (Paracetamol, Diclofenac and Tramadol) was pre- On examination, an erythematous perianal lesion was present scribed to provide pain relief for potential local skin reactions. with associated superficial excoriation (Fig. 1). An initial punch On review at the first 2 weeks of treatment, the patient had tol- biopsy was taken (Fig. 2A), which demonstrated a unilateral erated the imiquimod 5% cream, with only two applications well-demarcated eroded lesion. Immunohistochemical staining missed due to vomiting secondary to a viral infection. (Fig. 2B) showed malignant cells in the epidermis, staining posi- By Week 5, the area of erythema had visibly reduced, with a tively for CK7 and EMA. The tissue stained negative for CK20 and 1-cm rim of granulation tissue around its edge (Fig. 1B). The oestrogen receptors. A diagnosis of EMPD was given. patient’s progress was reviewed at 12 and 16 weeks, with a Breast and gynaecological examinations of the patient were stepwise regression of the EMPD identified. At 16-week examin- normal, while a colonoscopy did not identify any evidence of ation demonstrated almost complete resolution of the perianal extramammary bowel disease. A computed tomography (CT) erythema (Fig. 1C). Further multiple, random punch biopsies of chest, abdomen and pelvis demonstrated subcutaneous the perianal skin were taken 1 month later, which demon- strated variable evidence of chronic inflammation with epider- mal reaction (Fig. 2C), but no residual EMPD. A follow-up MRI of the pelvis 16 weeks after the discontinu- ation of treatment showed residual thickening consistent with inflammation at the site of previous subcutaneous nodules. A CT chest, abdomen and pelvis did not identify any distal EMPD deposits. The patient remained in remission for 18 months, however inguinal lymphadenopathy was noted at this time and a biopsy demonstrated adenocarcinoma suggesting malignant trans- formation of her EMPD. DISCUSSION We describe the primary local treatment of perianal EMPD with imiquimod 5% cream over a 16-week period initially resulting in remission prior to lymph node spread at 18 months. This provides further evidence, both in disease response and opti- Figure 1: (A) Initial presentation with an erythematous perianal lesion with mal treatment time, which imiquimod might potentially be associated superficial excoriation. (B) Appearance of rash following 5 weeks and considered as a first-line treatment for perineal EMPD. (C) 16 weeks of treatment with 5% imiquimod cream, demonstrating stepwise Imiquimod induces the immune response by activating improvement. (D) Appearance of perineum at 6-month follow-up following completion of treatment. macrophages and other inflammatory cells by increasing syn- thesis of pro-inflammatory cytokines while also producing distinctive apoptosis in epithelial cells [7]. A retrospective case- series of 23 patients demonstrated up to 80% clinical response with imiquimod for EMPD of the vulva [2]. The clinical response appears to be related to duration of imiquimod therapy in weeks [2]; however, the optimal length of treatment time remains to be defined. Surgical resection of perianal EMPD is an invasive procedure associated with a high perioperative morbidity. Furthermore, the potential of disfiguring surgery and permanent stoma for- mation may have a profound psychological impact on the patient. Recurrence rates could approach up to 50% despite Figure 2: (A) Initial punch biopsy of the perianal lesion demonstrated a well- adequate surgical resection margins [8]. demarcated erosive lesion with associated fibrin deposition and acute inflam- Close monitoring of patients during the treatment period is mation. (B) Following the 16-week course of imiquimod cream, repeat biopsies particularly important, both to monitor response of EMPD to demonstrated chronic inflammation with epidermal reaction and prominent treatment and the side-effect profile experienced by patients vascular proliferation, but no evidence of EMPD. Both produced with haema- toxylin & eosin staining. Scale bar 500 μm (A) and 200 μm (B). secondary to topical imiquimod. Following the completion of Extramammary Paget disease of the perianal region 3 imiquimod treatment, biopsies are mandatory in order to including gross cystic disease fluid protein-15 and cytokeratin assess residual disease, as recurrence is common. Longer term 20 expression. Arch Pathol Lab Med 1998;122:1077–81. data regarding recurrence following topical therapy, and 2. Luyten A, Sörgel P, Clad A, Gieseking F, Maass-Poppenhusen K, adequacy of subsequent surgical resection is awaited [6]. In this Lellé RJ, et al. Treatment of extramammary Paget disease of case recurrence was noted by palpable inguinal lymph nodes, the vulva with imiquimod: a retrospective, multicentre study with no skin or colonic lesion found. This highlights the by the German Colposcopy Network. JAm AcadDermatol importance of regular follow-up in perineal EMPD, with a high 2014;70:644–50. clinical index of suspicion for relapse or malignant change. 3. Goldblum JR, Hart WR. Perianal Paget’s disease: a histologic Developing an evidence-base for the use of imiquimod, as and immunohistochemical study of 19 cases. Am J Surg either first-line therapy or for disease recurrence, will be limited Pathol 1997;21:1178–87. by the potential number of new EMPD cases. An international 4. Wilkinson EJ, Brown HM. Vulvar Paget disease of urothelial register [9] to collate data on each patient case should be consid- origin: a report of three cases and a proposed classification ered to determine the optimal length of imiquimod treatment, of vulvar Paget disease. Hum Pathol 2002;33:549–54. together with the long-term follow-up of patients following 5. Luyten A, Brummer O, Kühnle H, Reinecke-Lüthge A, Petry treatment. In addition, it may also aid the identification of KU. New options for the treatment of Pagets disease of the patient cohorts most likely to respond to imiquimod therapy. vulva. Geburtshilfe Frauenheilkd 2006;66:1081–6. 6. Shaco-Levy R, Bean SM, Vollmer RT, Jewell E, Jones EL, Valdes CL, et al. Paget disease of the vulva: a study of CONFLICT OF INTEREST STATEMENT 56 cases. Eur J Obstet Gynecol Reprod Biol 2010;149:86–91. None declared. 7. Schon MP, Wienrich BG, Drewnlok C, Bong AB, Eberle J, Geilen CC, et al. Death receptor-independent apoptosis in PATIENT CONSENT malignant melanoma induced by the small-molecule immune response modifier imiquimod. J Invest Dermatol Written consent was gained from the patient prior to article 2004;122:1266–76. submission. 8. Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s disease. Br J Dermatol REFERENCES 2000;142:59–65. 9. Genetic and Rare Diseases Information Centre. http:// 1. Novak MA, Guerriere-Kovach P, Pathan A, Campbell TE, rarediseases.info.nih.gov/gard (22 April 2015, date last Deppisch LM. Perianal Paget’s disease: distinguishing primary accessed). and secondary lesions using immunohistological studies

Journal

Journal of Surgical Case Reports – Oxford University Press

Published: Aug 1, 2016

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