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Penoscrotal Extramammary Paget's Disease: The University of Texas M. D. Anderson Cancer Center Contemporary Experience
Penoscrotal Extramammary Paget’s Disease: The University of Texas M. D. Anderson Cancer Center Contemporary Experience Paul K. Hegarty, Jane Suh, Mark B. Fisher, Jennifer Taylor, Tri H. Nguyen, Doina Ivan, Victor G. Prieto, Lance C. Pagliaro and Curtis A. Pettaway* From the Departments of Urologic Oncology (PKH, JS, MBF, JT, CAP), Histopathology (DI, VGP) and Genitourinary Medical Oncology (LCP), University of Texas M. D. Anderson Cancer Center and Northwest Diagnostic Clinic P. A., Mohs and Dermatology Associates (THN), Houston, Texas
Purpose: Extramammary Paget’s disease is a rare intra-epithelial malignancy that is occasionally associated with an invasive adenocarcinoma component as well as other secondary cancers. We investigated a consecutive series of patients referred for extramammary Paget’s disease of the penis or scrotum at a single center in the contemporary era to determine the presence of secondary cancers and treatment outcomes. Materials and Methods: Between December 1990 and February 2009, 20 patients with extramammary Paget’s disease of the scrotum and/or penis were seen. Patients were investigated with computerized tomography of the abdomen/pelvis, chest x-ray, cystoscopy, colonoscopy and serum prostate specific antigen measurement to rule out obvious secondary cancer. Clinical charts were reviewed with institutional review board approval. Mean followup of treated cases was 48 months (range 7 to 208). Results: Patients were 50 to 86 years old with a history of symptoms of between 6 months and 10 years. Eight patients had invasive adenocarcinoma, of whom 2 died of the disease and 3 who had disease at 5, 7 and 40 months, respectively, were undergoing multimodal therapy. No patient with confirmed intra-epidermal disease only died of the disease. Invasive disease predicted nodal and metastatic progression. Conclusions: Surgical resection to achieve tumor-free margins resulted in durable relapse-free survival of patients with intra-epidermal extramammary Paget’s disease alone. Extramammary Paget’s disease with invasion was associated with regional metastatic progression. The latter scenario as well as failure to treat localized extramammary Paget’s disease alone was associated with a fatal outcome. Systemic chemotherapy should be further explored in patients with invasive adenocarcinoma or lymph node positive disease.
Abbreviations and Acronyms EMPD ⫽ extramammary Paget’s disease LVI ⫽ lymphovascular invasion WLE ⫽ wide local excision Submitted for publication July 23, 2010. Study received institutional review board approval. * Correspondence: Urology and Cancer Biology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030 (e-mail: [email protected]).
Key Words: penis, scrotum, Paget disease extramammary, Mohs surgery, neoplasm invasiveness EXTRAMAMMARY Paget’s disease is a rare intra-epithelial neoplasm that mostly arises in areas rich in apocrine sweat glands. Occasionally eccrine derived lesions may be noted. Disease onset is commonly insidious. Pruritus is often a major symptom and it may
precede the appearance of clinically detectable lesions.1 It presents as poorly defined or well demarcated erythematous, pruritic plaques that may become ulcerated, erosive, scaly or eczematous (fig. 1), or even pigmented. Even in well-defined tumors
0022-5347/11/1861-0097/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 97-102, July 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.02.2685
AND
RESEARCH, INC.
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endocervix or stomach.4,5 Penoscrotal EMPD may be associated with malignancy of the genitourinary tract, ie prostate, bladder and kidney.3,6 – 8 We describe our experience with clinical features, evaluation, traditional surgical excision and Mohs surgery as well as the response to multimodal therapy.
MATERIALS AND METHODS The institutional review board granted approval for this retrospective study. We reviewed the clinical charts of the 20 cases that presented between December 1990 and February 2009. All patients underwent computerized tomography of the abdomen/pelvis, chest x-ray, cystoscopy, and serum prostate specific antigen measurement to rule out genitourinary cancer. Colonoscopy was recommended to rule out colorectal malignancy.
Standard Surgical Excision
Figure 1. Gross appearance of scrotal EMPD
subclinical extension is a hallmark. Biopsy of the lesion usually reveals epidermal infiltration by a variable number of Paget’s cells, which have abundant, clear or sometimes eosinophilic cytoplasm and contain large vesicular, hypochromatic nuclei (fig. 2). The cells are present singly or in clusters and are usually scattered throughout all layers of the otherwise normal-appearing epidermis.1 These microscopic findings are pathognomonic for EMPD and distinguish it from Bowen’s disease, which may have a similar clinical presentation and gross appearance. The most common sites of EMPD include the vulva and perianal regions. Sites such as the male genitalia are less commonly reported with most cases described in Asia.2,3 EMPD is occasionally associated with an internal malignancy, such as carcinoma of the rectum, bladder, urethra, prostate,
Under general anesthesia the patient was placed in the low lithotomy position with Allen stirrups. A circumferential incision was made to encompass an area at least 1.0 to 1.5 cm away from any grossly visible abnormal areas of erythema on the skin. After removing the specimen it was oriented visually by placing surgical clips or marking sutures in designated areas and brought to the pathologist to clearly orient the specimen. Margin status on frozen section was not routinely assessed earlier in the series. However subsequently frozen section analysis became routine and upon identification of a positive margin a further ellipse of skin was excised in the positive area. Frozen sections were repeated until all margins were confirmed to be clear. Wound coverage was achieved by primary closure, skin grafting or rotational flap techniques.
Mohs Surgery Surgery was performed using local anesthesia. Scouting biopsies were taken preoperatively 1 to 2 cm peripheral to the outermost visible margin of the Paget’s lesion and distinctly marked with colored sutures (fig. 3). On the day of Mohs surgery the discernible tumor mass was excised as a horizontal layer using the Mohs technique. Tissue sections were precisely mapped, marked, processed with Mohs frozen histology and examined microscopically. Immunohistochemistry with cytokeratin-7 was routinely done during Mohs surgery to confirm final negative margins.
Figure 2. A, EMPD with intra-epithelial infiltration of vacuolated atypical cells and hyperkeratosis. B, Paget’s cells expressing cytokeratin-7. C, Paget’s cells highlighted with pan-cytokeratin antibody cocktail. Reduced from ⫻40.
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Figure 3. A, initial scout biopsies located 1 to 2 cm from visible lesion margin. B, sutured biopsy sites. C, combined Mohs surgery and wide local excision. Rim of tissue is excised using Mohs surgery to generate moat before excising intervening tissue.
Lymph Node Management The criterion for lymph node dissection was invasive adenocarcinoma in 9 patients in those with impalpable nodes. The 4 patients with positive nodes on lymphadenectomy were offered adjuvant chemotherapy. Chemotherapy regimens were selected for each patient by the treating oncologist (LCP). Patients with palpable lymph nodes underwent lymph node biopsy. Based on our experience with penile cancer9 patients with positive lymph nodes were offered neoadjuvant chemotherapy, followed by consolidative lymphadenectomy in 2.
Followup Five patients elected treatment elsewhere, mostly due to distance from home, and in 1 followup was less than 6 months. The remaining 14 patients were treated and followed a mean of 48 months (range 7 to 208). Data were analyzed and illustrated using Microsoft® Office Excel®. Categorical variables were compared by the Pearson chisquare test with significance considered at p ⬍0.05.
RESULTS Characteristics and Associated Cancers Patients were 50 to 86 years old. By race 14 patients were nonHispanic white, 4 were Asian and 2 were Hispanic. Nine of the 20 patients (45%) had at least 1 other malignancy, including prostate cancer in 4, superficial bladder cancer in 1, renal cell cancer in 1, nonmelanoma skin cancer in 4, esophageal cancer in 1 and rectal cancer in 1. Some patients had more than 2 cancers. No patient died of the second malignancy during followup. Except for 1 patient with prostate cancer the remaining patients were diagnosed with the other malignancy before the EMPD diagnosis. No colonic malignancy was found in any of the 20 cases upon presentation with EMPD. One man was found to have rectal cancer arising from a tubular adenoma on colonoscopy before the EMPD diagnosis. Tubular adenomas were found in 2 men and benign polyps in another 2 on colonoscopy. Inguinal/scrotal pruritis and color change were the predominant symptoms at presentation. Patients had a median symptom history of 2 years (range 3 months to 15 years). There was a trend toward a
longer symptom history in patients with invasive EMPD compared to that in patients with noninvasive disease (4.25 vs 2.25 years, 2-tailed Student t test p ⫽ 0.24). Primary Tumor Treatment Mean followup was 48 months (range 7 to 208). One patient was referred after WLE identified a positive margin. He elected radiotherapy and had no evidence of disease at 82-month followup. Of the 14 patients treated at M. D. Anderson Cancer Center the tumor was excised by the Mohs technique in 4, by WLE in 8, and by combining the Mohs technique for the margin and standard excision for the center in 1 (fig. 3). Two of the 8 patients who underwent WLE had a positive margin. This was earlier in the series when frozen sections were not routine. These patients refused further surgery and received adjuvant radiotherapy. Patient 12 underwent biopsy only of the primary lesion. He received chemotherapy and died of disease at 31 months. No case performed using the Mohs technique had a positive margin. Nine patients required plastic surgical closure using rotation flaps or skin grafting. Regardless of the excisional technique no patient had local recurrence during followup. Treatment Outcomes The table lists treatments and outcomes. No patient with intra-epidermal EMPD had positive lymph nodes or distant metastasis. Patient 4 elected surgery elsewhere and died of an acute cardiac event postoperatively. The remaining 7 patients with intra-epidermal EMPD had no nodal or distant metastasis at a mean of 62 months of followup (range 11 to 126). Extramammary Paget’s Disease Invasive. Median disease specific survival was significantly poorer in patients with invasive EMPD compared to the ongoing median survival in those with intra-epidermal adenocarcinoma (14.5 vs 55 months). Five of the 10 patients with confirmed invasive disease had lymph node metastasis, including 4 with
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Overall survival by disease stage and treatment Pt No.
Primary Treatment
Primary Stage
Margin Status
1 2 3 4 5 6 7
WLE Elsewhere WLE Elsewhere Mohs surgery Mohs surgery WLE/Mohs surgery Mohs surgery WLE
Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal
Neg Neg Neg Unknown Neg Neg Neg
No No Yes No No No No
Neg Neg Neg Neg Neg Neg Neg
Neg Neg Neg Unknown Neg Neg Neg
Neg Neg Neg Neg Neg Neg Neg
No No No No No No No
No disease evidence (66) No disease evidence (106) No disease evidence (126) Died of postop cardiac event No disease evidence (26) No disease evidence (47) No disease evidence (11)
Intra-epidermal Micro-invasive
Neg Neg
No No
Neg Pos
Neg Pos
Neg Liver
No disease evidence (55) Disease (5)
10 11
WLE WLE
Micro-invasive Invasive
Pos Neg
No Yes
Neg Pos
Neg Pos
Neg Neg
12 13 14 15 16
Biopsy WLE Elsewhere Mohs surgery WLE
Invasive Invasive Invasive Invasive Invasive
Unknown Pos Unknown Neg Neg
Yes Yes Unknown No Yes
Pos Neg Neg Neg Neg
Pos Pos Neg Neg Pos
Para-aortic nodes Para-aortic nodes Neg Neg Neg
17
WLE
Invasive
Neg
Yes
Neg
Pos
18 19 20
Elsewhere Elsewhere Elsewhere
Invasive Unknown Unknown
Pos Unknown Unknown
Unknown Unknown Unknown
Neg Unknown Neg
Unknown Unknown Pos
Liver, peri-aortic nodes Neg Neg Pulmonary
No Palliative chemotherapy Radiotherapy Neoadjuvant chemotherapy Chemotherapy Radiotherapy No No Neoadjuvant chemotherapy Chemotherapy
8 9
Lymph Node Dissection
LVI
distant metastasis (each significant vs intra-epidermal EMPD, chi-square test p ⬍0.05). Patient 18 was referred after a positive surgical margin was found elsewhere. He refused further surgery or adjuvant radiotherapy and died 12 months later. Three of the 10 patients with invasive disease died of disease. Two cases of invasion were termed microinvasion with a focus of invasion of less than 0.5 mm, including patient 9 with LVI, positive inguinal and pelvic lymph nodes, and liver metastasis. Palliative chemotherapy was recommended. The other man (patient 10) did not have LVI, or nodal or metastatic disease until he died of other causes 208 months after presentation. In this series 2 patients received neoadjuvant chemotherapy and underwent consolidative lymph node dissection. Patient 11 underwent 3 cycles of docetaxel before consolidative inguinal and pelvic lymph node dissection. Of the 43 nodes removed 20 had residual cancer. He was alive with disease 40 months after presentation. In patient 16 EMPD and prostate cancer were diagnosed before referral. The primary skin lesion was excised, followed by radical retropubic prostatectomy, at which 2 of 3 pelvic nodes were found to harbor metastatic deposits of EMPD. At referral computerized tomography revealed enlarged inguinal lymph nodes. He had a complete radiological response to 3 cycles of docetaxel and carboplatin. He underwent bilateral inguinal lymphadenectomy and none of the 25 nodes
Nodal Status
Metastasis
Adjuvant Therapy
Pt refused Unknown Unknown
Survival (mos)
Died of other disease (208) Disease (40) Died (31) Died (16) No disease evidence (58) No disease evidence (8) No disease evidence (13) Disease (7) Died (12) No disease evidence (10) Died (15)
showed any cancer. He remained free of disease at 13-month followup. LVI was present in 3 patients, who all had nodal disease and distant metastasis. However, another 3 patients also had positive lymph nodes without LVI in the primary specimen. In invasive EMPD cases LVI did not independently predict lymph node disease or metastatic disease (chi-square test p ⫽ 0.13 and 0.26, respectively). Indeterminate. Since 2 patients underwent biopsy elsewhere, the entire specimens were not available to determine invasion. One patient died of metastatic disease 15 months after presentation.
DISCUSSION To our knowledge staging, prognosis and response to treatment for EMPD have yet to be defined due to the rarity of the disease. Our goal was to define these parameters in a cohort of patients treated at a large tertiary referral center during 19 years to define factors associated with cure of the disease and better define therapeutic challenges. To our knowledge our 20 patients represent the largest series to date of penoscrotal EMPD in the United States. Nine of the 20 patients had another primary malignancy, of which all except 1 were diagnosed before presentation with EMPD. Colonoscopy did not reveal any malignancy, although 2 cases of tubulovillous adenoma were identified.
PENOSCROTAL EXTRAMAMMARY PAGET’S DISEASE
This is similar to other series, in which investigating the gastrointestinal tract in patients with penoscrotal EMPD did not show any new malignancy.1,10 Thus, except for an indication for screening colonoscopy in a patient who is otherwise asymptomatic, routine colonoscopy to look for secondary colon cancer may not be indicated. Our data set demonstrates distinct prognoses for those with or without invasive adenocarcinoma. In the single patient (patient 20) with seemingly noninvasive cancer in whom lymph node disease developed the diagnosis was based on biopsy only. This underscores the need for complete excision to accurately define disease extent. There was a trend toward those with invasive pathological findings to have had a longer symptom history. This implies that intra-epidermal EMPD may progress to the invasive type if left untreated. We noted that achieving clear margins is essential to control the disease in patients without invasive adenocarcinoma. In other studies positive margins were associated with local recurrence.2 In 2 patients with a positive margin after WLE disease was controlled by adjuvant radiotherapy, while a third patient who refused surgery or radiotherapy for a positive margin died 12 months later. Thus, achieving local control is paramount to long-term survival even in patients with initially intra-epidermal disease since it appears to prevent further invasion and metastasis. EMPD is insidious, in that malignant cells can spread far beyond the grossly evident lesion. A report of 36 cases of penoscrotal EMPD showed that excision with a margin of 1 to 2 cm on gross examination yielded a 73.9% positive margin rate while intraoperative frozen section decreased the margin rate to 7.7%.11 Most reports of EMPD are from patient series collected from Asian cohorts. In a retrospective series of 130 patients with genital EMPD from China local recurrence was associated with positive margins. In our series no patient had local recurrence. The incidence of EMPD in The Netherlands between 1989 and 2001 is described in its national cancer database.12 During the 13 years 1,629 cases of Paget’s disease were documented, of which 226 were EMPD. Of the 78 men 28 (36%) had genital EMPD. In 2000 the male population of The Netherlands was 7.8 million individuals.13 Thus, the incidence is calculated to be 1/3.7 million males annually. The choice of surgical approach was addressed in a retrospective review from Mayo Clinic.14 A total of 95 patients were treated, including 83 with WLE and 12 with Mohs surgery. The local recurrence rate was 22% in those with WLE vs 8% in those with Mohs excision. Mohs surgery appears to be well
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suited to Paget’s disease since the tumor has indistinct margins. In our study the number of cases was too small to compare Mohs surgery with traditional surgical excision. However, we agree that the Mohs technique used by experienced dermatologists appears to be an effective alternative to traditional surgery. For larger EMPD tumors a combined approach may be best. Using local anesthesia Mohs surgery is first performed to clear the peripheral margins, leaving the central tumor intact and creating a moat-like wound (fig. 3, C). After the peripheral margins are clear and with the patient under general anesthesia the central tumor may then be resected by the oncological surgeon. Poor prognostic features in EMPD cohorts include invasive disease/underlying dermal adenocarcinoma, internal carcinoma, LVI and lymph node metastasis.15,16 We observed that invasive disease is associated with lymph node metastasis and poorer survival. Such cases may benefit from multimodal therapy. In this series neoadjuvant chemotherapy was given to 2 patients. One patient achieved a complete pathological response with no evidence of recurrence at 13-month postoperative followup while the other achieved prolonged survival with disease at 40-month followup. There are insufficient data to establish the superiority of any specific chemotherapy over another for EMPD. In our series a taxane (docetaxel) was chosen since it has efficacy for a wide range of epithelial tumors, and is well tolerated and suitable for outpatient administration. Although docetaxel alone had some effect, we subsequently selected docetaxel plus carboplatin largely on empirical grounds to improve tumor control and found a complete response in 1 case. There are reports of using docetaxel in 2 patients,17 5-fluorouracil and cisplatin in 1,18 and mitomycin-C, vincristine, 5-fluorouracil and cisplatin in 2.19 These reports underline the rarity of this cancer and the potential role of multimodal therapy to achieve palliation.
CONCLUSIONS Extramammary Paget’s disease of the penoscrotal region is a rare disease. We recommend screening the genitourinary tract and reserving colonoscopy mainly for patients who have not undergone a screening study in the last 5 years or who show symptoms. Prognosis is excellent for patients without invasive disease provided that complete excision with a negative margin is achieved by traditional frozen section or the Mohs technique. Patients with invasive adenocarcinoma have a
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poorer prognosis and prophylactic inguinal node dissection could be considered in select patients with no palpable inguinal adenopathy. The role of neoadjuvant chemotherapy with consolidative
surgery should be further explored in patients with demonstrable lymph node involvement. The latter would potentially be feasible via a multicenter clinical trial.
REFERENCES 1. Park S, Grossfeld GD, McAninch JW et al: Extramammary Paget’s disease of the penis and scrotum: excision, reconstruction and evaluation of occult malignancy. J Urol 2001; 166: 2112. 2. Wang Z, Lu M, Dong GQ et al: Penile and scrotal Paget’s disease: 130 Chinese patients with longterm follow-up. BJU Int 2008; 102: 485. 3. Chanda JJ: Extramammary Paget’s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13: 1009. 4. Im M, Kye KC, Kim JM et al: Extramammary Paget’s disease of the scrotum with adenocarcinoma of the stomach. J Am Acad Dermatol 2007; 57: S43. 5. Lai YL, Yang WG, Tsay PW et al: Penoscrotal extramammary Paget’s disease: a review of 33 cases in a 20-year experience. Plast Reconstr Surg 2003; 112: 1017. 6. Ojeda VJ, Heenan PJ and Watson SH: Paget’s disease of the groin associated with adenocarcinoma of the urinary bladder. J Cutan Pathol 1987; 14: 227. 7. Koh KBH and Nazarina AR: Paget’s disease of the scrotum: report of a case with underlying carcinoma of the prostate. Br J Dermatol 1995; 133: 306.
8. Allan SJR, McLaren K and Aldridge RD: Paget’s disease of the scrotum: a case exhibiting positive prostate-specific antigen staining and associated with prostatic adenocarcinoma. Br J Dermatol 1998; 138: 689. 9. Bermejo C, Busby JE, Spiess PE et al: Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007; 177: 1335. 10. Chiu TW, Wong PSY, Ahmed K et al: Extramammary Paget’s disease in Chinese males: a 21-year experience. World J Surg 2007; 31: 1941. 11. Yang WJ, Kim DS, Im YJ et al: Extramammary Paget’s disease of penis and scrotum. Urology 2005; 65: 972. 12. Siesling S, Elferink MA, van Dijck JA et al: Epidemiology and treatment of extramammary Paget disease in the Netherlands. Eur J Surg Oncol 2007; 33: 951. 13. World Population Ageing 1950-2050: Netherlands. Population Division, Department of Economic and Social Affairs, United Nations. Available at http://www.un.org/esa/population/publications/ worldageing19502050/pdf/149nethe.pdf. Accessed February 2, 2009.
14. O’Connor WJ, Lim KK, Zalla MJ et al: Comparison of Mohs micrographical surgery and wide excision for extramammary Paget’s disease. Dermatol Surg 2003; 29: 723. 15. 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. 16. Choi YD, Cho NH, Park YS et al: Lymphovascular and margin invasion are useful prognostic indicators and the role of c-erbB-2 in patients with male extramammary Paget’s disease: a study of 31 cases. J Urol 2005; 174: 561. 17. Oguchi S, Kaneko M, Uhara H et al: Docetaxel induced durable response in advanced extramammary Paget’s disease: a case report. J Dermatol 2002; 29: 33. 18. Kariya K, Tsuji T and Schwartz RA: Trial of lowdose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget’s disease. Dermatol Surg 2004; 30: 341. 19. Mochitomi Y, Sakamoto R, Gushi A et al: Extramammary Paget’s disease/carcinoma successfully treated with a combination chemotherapy: report of two cases. J Dermatol 2005; 32: 632.
Purpose: Extramammary Paget’s disease is a rare intra-epithelial malignancy that is occasionally associated with an invasive adenocarcinoma component as well as other secondary cancers. We investigated a consecutive series of patients referred for extramammary Paget’s disease of the penis or scrotum at a single center in the contemporary era to determine the presence of secondary cancers and treatment outcomes. Materials and Methods: Between December 1990 and February 2009, 20 patients with extramammary Paget’s disease of the scrotum and/or penis were seen. Patients were investigated with computerized tomography of the abdomen/pelvis, chest x-ray, cystoscopy, colonoscopy and serum prostate specific antigen measurement to rule out obvious secondary cancer. Clinical charts were reviewed with institutional review board approval. Mean followup of treated cases was 48 months (range 7 to 208). Results: Patients were 50 to 86 years old with a history of symptoms of between 6 months and 10 years. Eight patients had invasive adenocarcinoma, of whom 2 died of the disease and 3 who had disease at 5, 7 and 40 months, respectively, were undergoing multimodal therapy. No patient with confirmed intra-epidermal disease only died of the disease. Invasive disease predicted nodal and metastatic progression. Conclusions: Surgical resection to achieve tumor-free margins resulted in durable relapse-free survival of patients with intra-epidermal extramammary Paget’s disease alone. Extramammary Paget’s disease with invasion was associated with regional metastatic progression. The latter scenario as well as failure to treat localized extramammary Paget’s disease alone was associated with a fatal outcome. Systemic chemotherapy should be further explored in patients with invasive adenocarcinoma or lymph node positive disease.
Abbreviations and Acronyms EMPD ⫽ extramammary Paget’s disease LVI ⫽ lymphovascular invasion WLE ⫽ wide local excision Submitted for publication July 23, 2010. Study received institutional review board approval. * Correspondence: Urology and Cancer Biology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030 (e-mail: [email protected]).
Key Words: penis, scrotum, Paget disease extramammary, Mohs surgery, neoplasm invasiveness EXTRAMAMMARY Paget’s disease is a rare intra-epithelial neoplasm that mostly arises in areas rich in apocrine sweat glands. Occasionally eccrine derived lesions may be noted. Disease onset is commonly insidious. Pruritus is often a major symptom and it may
precede the appearance of clinically detectable lesions.1 It presents as poorly defined or well demarcated erythematous, pruritic plaques that may become ulcerated, erosive, scaly or eczematous (fig. 1), or even pigmented. Even in well-defined tumors
0022-5347/11/1861-0097/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 97-102, July 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.02.2685
AND
RESEARCH, INC.
www.jurology.com
97
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endocervix or stomach.4,5 Penoscrotal EMPD may be associated with malignancy of the genitourinary tract, ie prostate, bladder and kidney.3,6 – 8 We describe our experience with clinical features, evaluation, traditional surgical excision and Mohs surgery as well as the response to multimodal therapy.
MATERIALS AND METHODS The institutional review board granted approval for this retrospective study. We reviewed the clinical charts of the 20 cases that presented between December 1990 and February 2009. All patients underwent computerized tomography of the abdomen/pelvis, chest x-ray, cystoscopy, and serum prostate specific antigen measurement to rule out genitourinary cancer. Colonoscopy was recommended to rule out colorectal malignancy.
Standard Surgical Excision
Figure 1. Gross appearance of scrotal EMPD
subclinical extension is a hallmark. Biopsy of the lesion usually reveals epidermal infiltration by a variable number of Paget’s cells, which have abundant, clear or sometimes eosinophilic cytoplasm and contain large vesicular, hypochromatic nuclei (fig. 2). The cells are present singly or in clusters and are usually scattered throughout all layers of the otherwise normal-appearing epidermis.1 These microscopic findings are pathognomonic for EMPD and distinguish it from Bowen’s disease, which may have a similar clinical presentation and gross appearance. The most common sites of EMPD include the vulva and perianal regions. Sites such as the male genitalia are less commonly reported with most cases described in Asia.2,3 EMPD is occasionally associated with an internal malignancy, such as carcinoma of the rectum, bladder, urethra, prostate,
Under general anesthesia the patient was placed in the low lithotomy position with Allen stirrups. A circumferential incision was made to encompass an area at least 1.0 to 1.5 cm away from any grossly visible abnormal areas of erythema on the skin. After removing the specimen it was oriented visually by placing surgical clips or marking sutures in designated areas and brought to the pathologist to clearly orient the specimen. Margin status on frozen section was not routinely assessed earlier in the series. However subsequently frozen section analysis became routine and upon identification of a positive margin a further ellipse of skin was excised in the positive area. Frozen sections were repeated until all margins were confirmed to be clear. Wound coverage was achieved by primary closure, skin grafting or rotational flap techniques.
Mohs Surgery Surgery was performed using local anesthesia. Scouting biopsies were taken preoperatively 1 to 2 cm peripheral to the outermost visible margin of the Paget’s lesion and distinctly marked with colored sutures (fig. 3). On the day of Mohs surgery the discernible tumor mass was excised as a horizontal layer using the Mohs technique. Tissue sections were precisely mapped, marked, processed with Mohs frozen histology and examined microscopically. Immunohistochemistry with cytokeratin-7 was routinely done during Mohs surgery to confirm final negative margins.
Figure 2. A, EMPD with intra-epithelial infiltration of vacuolated atypical cells and hyperkeratosis. B, Paget’s cells expressing cytokeratin-7. C, Paget’s cells highlighted with pan-cytokeratin antibody cocktail. Reduced from ⫻40.
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Figure 3. A, initial scout biopsies located 1 to 2 cm from visible lesion margin. B, sutured biopsy sites. C, combined Mohs surgery and wide local excision. Rim of tissue is excised using Mohs surgery to generate moat before excising intervening tissue.
Lymph Node Management The criterion for lymph node dissection was invasive adenocarcinoma in 9 patients in those with impalpable nodes. The 4 patients with positive nodes on lymphadenectomy were offered adjuvant chemotherapy. Chemotherapy regimens were selected for each patient by the treating oncologist (LCP). Patients with palpable lymph nodes underwent lymph node biopsy. Based on our experience with penile cancer9 patients with positive lymph nodes were offered neoadjuvant chemotherapy, followed by consolidative lymphadenectomy in 2.
Followup Five patients elected treatment elsewhere, mostly due to distance from home, and in 1 followup was less than 6 months. The remaining 14 patients were treated and followed a mean of 48 months (range 7 to 208). Data were analyzed and illustrated using Microsoft® Office Excel®. Categorical variables were compared by the Pearson chisquare test with significance considered at p ⬍0.05.
RESULTS Characteristics and Associated Cancers Patients were 50 to 86 years old. By race 14 patients were nonHispanic white, 4 were Asian and 2 were Hispanic. Nine of the 20 patients (45%) had at least 1 other malignancy, including prostate cancer in 4, superficial bladder cancer in 1, renal cell cancer in 1, nonmelanoma skin cancer in 4, esophageal cancer in 1 and rectal cancer in 1. Some patients had more than 2 cancers. No patient died of the second malignancy during followup. Except for 1 patient with prostate cancer the remaining patients were diagnosed with the other malignancy before the EMPD diagnosis. No colonic malignancy was found in any of the 20 cases upon presentation with EMPD. One man was found to have rectal cancer arising from a tubular adenoma on colonoscopy before the EMPD diagnosis. Tubular adenomas were found in 2 men and benign polyps in another 2 on colonoscopy. Inguinal/scrotal pruritis and color change were the predominant symptoms at presentation. Patients had a median symptom history of 2 years (range 3 months to 15 years). There was a trend toward a
longer symptom history in patients with invasive EMPD compared to that in patients with noninvasive disease (4.25 vs 2.25 years, 2-tailed Student t test p ⫽ 0.24). Primary Tumor Treatment Mean followup was 48 months (range 7 to 208). One patient was referred after WLE identified a positive margin. He elected radiotherapy and had no evidence of disease at 82-month followup. Of the 14 patients treated at M. D. Anderson Cancer Center the tumor was excised by the Mohs technique in 4, by WLE in 8, and by combining the Mohs technique for the margin and standard excision for the center in 1 (fig. 3). Two of the 8 patients who underwent WLE had a positive margin. This was earlier in the series when frozen sections were not routine. These patients refused further surgery and received adjuvant radiotherapy. Patient 12 underwent biopsy only of the primary lesion. He received chemotherapy and died of disease at 31 months. No case performed using the Mohs technique had a positive margin. Nine patients required plastic surgical closure using rotation flaps or skin grafting. Regardless of the excisional technique no patient had local recurrence during followup. Treatment Outcomes The table lists treatments and outcomes. No patient with intra-epidermal EMPD had positive lymph nodes or distant metastasis. Patient 4 elected surgery elsewhere and died of an acute cardiac event postoperatively. The remaining 7 patients with intra-epidermal EMPD had no nodal or distant metastasis at a mean of 62 months of followup (range 11 to 126). Extramammary Paget’s Disease Invasive. Median disease specific survival was significantly poorer in patients with invasive EMPD compared to the ongoing median survival in those with intra-epidermal adenocarcinoma (14.5 vs 55 months). Five of the 10 patients with confirmed invasive disease had lymph node metastasis, including 4 with
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Overall survival by disease stage and treatment Pt No.
Primary Treatment
Primary Stage
Margin Status
1 2 3 4 5 6 7
WLE Elsewhere WLE Elsewhere Mohs surgery Mohs surgery WLE/Mohs surgery Mohs surgery WLE
Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal Intra-epidermal
Neg Neg Neg Unknown Neg Neg Neg
No No Yes No No No No
Neg Neg Neg Neg Neg Neg Neg
Neg Neg Neg Unknown Neg Neg Neg
Neg Neg Neg Neg Neg Neg Neg
No No No No No No No
No disease evidence (66) No disease evidence (106) No disease evidence (126) Died of postop cardiac event No disease evidence (26) No disease evidence (47) No disease evidence (11)
Intra-epidermal Micro-invasive
Neg Neg
No No
Neg Pos
Neg Pos
Neg Liver
No disease evidence (55) Disease (5)
10 11
WLE WLE
Micro-invasive Invasive
Pos Neg
No Yes
Neg Pos
Neg Pos
Neg Neg
12 13 14 15 16
Biopsy WLE Elsewhere Mohs surgery WLE
Invasive Invasive Invasive Invasive Invasive
Unknown Pos Unknown Neg Neg
Yes Yes Unknown No Yes
Pos Neg Neg Neg Neg
Pos Pos Neg Neg Pos
Para-aortic nodes Para-aortic nodes Neg Neg Neg
17
WLE
Invasive
Neg
Yes
Neg
Pos
18 19 20
Elsewhere Elsewhere Elsewhere
Invasive Unknown Unknown
Pos Unknown Unknown
Unknown Unknown Unknown
Neg Unknown Neg
Unknown Unknown Pos
Liver, peri-aortic nodes Neg Neg Pulmonary
No Palliative chemotherapy Radiotherapy Neoadjuvant chemotherapy Chemotherapy Radiotherapy No No Neoadjuvant chemotherapy Chemotherapy
8 9
Lymph Node Dissection
LVI
distant metastasis (each significant vs intra-epidermal EMPD, chi-square test p ⬍0.05). Patient 18 was referred after a positive surgical margin was found elsewhere. He refused further surgery or adjuvant radiotherapy and died 12 months later. Three of the 10 patients with invasive disease died of disease. Two cases of invasion were termed microinvasion with a focus of invasion of less than 0.5 mm, including patient 9 with LVI, positive inguinal and pelvic lymph nodes, and liver metastasis. Palliative chemotherapy was recommended. The other man (patient 10) did not have LVI, or nodal or metastatic disease until he died of other causes 208 months after presentation. In this series 2 patients received neoadjuvant chemotherapy and underwent consolidative lymph node dissection. Patient 11 underwent 3 cycles of docetaxel before consolidative inguinal and pelvic lymph node dissection. Of the 43 nodes removed 20 had residual cancer. He was alive with disease 40 months after presentation. In patient 16 EMPD and prostate cancer were diagnosed before referral. The primary skin lesion was excised, followed by radical retropubic prostatectomy, at which 2 of 3 pelvic nodes were found to harbor metastatic deposits of EMPD. At referral computerized tomography revealed enlarged inguinal lymph nodes. He had a complete radiological response to 3 cycles of docetaxel and carboplatin. He underwent bilateral inguinal lymphadenectomy and none of the 25 nodes
Nodal Status
Metastasis
Adjuvant Therapy
Pt refused Unknown Unknown
Survival (mos)
Died of other disease (208) Disease (40) Died (31) Died (16) No disease evidence (58) No disease evidence (8) No disease evidence (13) Disease (7) Died (12) No disease evidence (10) Died (15)
showed any cancer. He remained free of disease at 13-month followup. LVI was present in 3 patients, who all had nodal disease and distant metastasis. However, another 3 patients also had positive lymph nodes without LVI in the primary specimen. In invasive EMPD cases LVI did not independently predict lymph node disease or metastatic disease (chi-square test p ⫽ 0.13 and 0.26, respectively). Indeterminate. Since 2 patients underwent biopsy elsewhere, the entire specimens were not available to determine invasion. One patient died of metastatic disease 15 months after presentation.
DISCUSSION To our knowledge staging, prognosis and response to treatment for EMPD have yet to be defined due to the rarity of the disease. Our goal was to define these parameters in a cohort of patients treated at a large tertiary referral center during 19 years to define factors associated with cure of the disease and better define therapeutic challenges. To our knowledge our 20 patients represent the largest series to date of penoscrotal EMPD in the United States. Nine of the 20 patients had another primary malignancy, of which all except 1 were diagnosed before presentation with EMPD. Colonoscopy did not reveal any malignancy, although 2 cases of tubulovillous adenoma were identified.
PENOSCROTAL EXTRAMAMMARY PAGET’S DISEASE
This is similar to other series, in which investigating the gastrointestinal tract in patients with penoscrotal EMPD did not show any new malignancy.1,10 Thus, except for an indication for screening colonoscopy in a patient who is otherwise asymptomatic, routine colonoscopy to look for secondary colon cancer may not be indicated. Our data set demonstrates distinct prognoses for those with or without invasive adenocarcinoma. In the single patient (patient 20) with seemingly noninvasive cancer in whom lymph node disease developed the diagnosis was based on biopsy only. This underscores the need for complete excision to accurately define disease extent. There was a trend toward those with invasive pathological findings to have had a longer symptom history. This implies that intra-epidermal EMPD may progress to the invasive type if left untreated. We noted that achieving clear margins is essential to control the disease in patients without invasive adenocarcinoma. In other studies positive margins were associated with local recurrence.2 In 2 patients with a positive margin after WLE disease was controlled by adjuvant radiotherapy, while a third patient who refused surgery or radiotherapy for a positive margin died 12 months later. Thus, achieving local control is paramount to long-term survival even in patients with initially intra-epidermal disease since it appears to prevent further invasion and metastasis. EMPD is insidious, in that malignant cells can spread far beyond the grossly evident lesion. A report of 36 cases of penoscrotal EMPD showed that excision with a margin of 1 to 2 cm on gross examination yielded a 73.9% positive margin rate while intraoperative frozen section decreased the margin rate to 7.7%.11 Most reports of EMPD are from patient series collected from Asian cohorts. In a retrospective series of 130 patients with genital EMPD from China local recurrence was associated with positive margins. In our series no patient had local recurrence. The incidence of EMPD in The Netherlands between 1989 and 2001 is described in its national cancer database.12 During the 13 years 1,629 cases of Paget’s disease were documented, of which 226 were EMPD. Of the 78 men 28 (36%) had genital EMPD. In 2000 the male population of The Netherlands was 7.8 million individuals.13 Thus, the incidence is calculated to be 1/3.7 million males annually. The choice of surgical approach was addressed in a retrospective review from Mayo Clinic.14 A total of 95 patients were treated, including 83 with WLE and 12 with Mohs surgery. The local recurrence rate was 22% in those with WLE vs 8% in those with Mohs excision. Mohs surgery appears to be well
101
suited to Paget’s disease since the tumor has indistinct margins. In our study the number of cases was too small to compare Mohs surgery with traditional surgical excision. However, we agree that the Mohs technique used by experienced dermatologists appears to be an effective alternative to traditional surgery. For larger EMPD tumors a combined approach may be best. Using local anesthesia Mohs surgery is first performed to clear the peripheral margins, leaving the central tumor intact and creating a moat-like wound (fig. 3, C). After the peripheral margins are clear and with the patient under general anesthesia the central tumor may then be resected by the oncological surgeon. Poor prognostic features in EMPD cohorts include invasive disease/underlying dermal adenocarcinoma, internal carcinoma, LVI and lymph node metastasis.15,16 We observed that invasive disease is associated with lymph node metastasis and poorer survival. Such cases may benefit from multimodal therapy. In this series neoadjuvant chemotherapy was given to 2 patients. One patient achieved a complete pathological response with no evidence of recurrence at 13-month postoperative followup while the other achieved prolonged survival with disease at 40-month followup. There are insufficient data to establish the superiority of any specific chemotherapy over another for EMPD. In our series a taxane (docetaxel) was chosen since it has efficacy for a wide range of epithelial tumors, and is well tolerated and suitable for outpatient administration. Although docetaxel alone had some effect, we subsequently selected docetaxel plus carboplatin largely on empirical grounds to improve tumor control and found a complete response in 1 case. There are reports of using docetaxel in 2 patients,17 5-fluorouracil and cisplatin in 1,18 and mitomycin-C, vincristine, 5-fluorouracil and cisplatin in 2.19 These reports underline the rarity of this cancer and the potential role of multimodal therapy to achieve palliation.
CONCLUSIONS Extramammary Paget’s disease of the penoscrotal region is a rare disease. We recommend screening the genitourinary tract and reserving colonoscopy mainly for patients who have not undergone a screening study in the last 5 years or who show symptoms. Prognosis is excellent for patients without invasive disease provided that complete excision with a negative margin is achieved by traditional frozen section or the Mohs technique. Patients with invasive adenocarcinoma have a
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PENOSCROTAL EXTRAMAMMARY PAGET’S DISEASE
poorer prognosis and prophylactic inguinal node dissection could be considered in select patients with no palpable inguinal adenopathy. The role of neoadjuvant chemotherapy with consolidative
surgery should be further explored in patients with demonstrable lymph node involvement. The latter would potentially be feasible via a multicenter clinical trial.
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8. Allan SJR, McLaren K and Aldridge RD: Paget’s disease of the scrotum: a case exhibiting positive prostate-specific antigen staining and associated with prostatic adenocarcinoma. Br J Dermatol 1998; 138: 689. 9. Bermejo C, Busby JE, Spiess PE et al: Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007; 177: 1335. 10. Chiu TW, Wong PSY, Ahmed K et al: Extramammary Paget’s disease in Chinese males: a 21-year experience. World J Surg 2007; 31: 1941. 11. Yang WJ, Kim DS, Im YJ et al: Extramammary Paget’s disease of penis and scrotum. Urology 2005; 65: 972. 12. Siesling S, Elferink MA, van Dijck JA et al: Epidemiology and treatment of extramammary Paget disease in the Netherlands. Eur J Surg Oncol 2007; 33: 951. 13. World Population Ageing 1950-2050: Netherlands. Population Division, Department of Economic and Social Affairs, United Nations. Available at http://www.un.org/esa/population/publications/ worldageing19502050/pdf/149nethe.pdf. Accessed February 2, 2009.
14. O’Connor WJ, Lim KK, Zalla MJ et al: Comparison of Mohs micrographical surgery and wide excision for extramammary Paget’s disease. Dermatol Surg 2003; 29: 723. 15. 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. 16. Choi YD, Cho NH, Park YS et al: Lymphovascular and margin invasion are useful prognostic indicators and the role of c-erbB-2 in patients with male extramammary Paget’s disease: a study of 31 cases. J Urol 2005; 174: 561. 17. Oguchi S, Kaneko M, Uhara H et al: Docetaxel induced durable response in advanced extramammary Paget’s disease: a case report. J Dermatol 2002; 29: 33. 18. Kariya K, Tsuji T and Schwartz RA: Trial of lowdose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget’s disease. Dermatol Surg 2004; 30: 341. 19. Mochitomi Y, Sakamoto R, Gushi A et al: Extramammary Paget’s disease/carcinoma successfully treated with a combination chemotherapy: report of two cases. J Dermatol 2005; 32: 632.