Evidence-Based Clinical Practice Guidelines for Extramammary Paget Disease

Abstract

disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE To develop recommendations for the care of adults with EMPD.EVIDENCE REVIEW A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGSThe key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. ( 5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.CONCLUSIONS AND RELEVANCE Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

Treatment of Metastatic Primary Extramammary Paget Disease With Combination Anlotinib and Tislelizumab: A Case Report and Review of the Literature

“…Chemotherapy remains the cornerstone of EMPD management. However, there is currently no standardized treatment for metastasis ( 11 , 12 ). Kato et al retrospectively analyzed 17 EMPD patients with multiple metastases, of which eight were treated with 5-fluoruuracil (FU)/cisplatin and nine patients chose best supportive care ( 13 ).…”

“…Evidence-Based Clinical Practice Guidelines recommends chemotherapy, targeted therapy or immune checkpoint inhibitors for patients with metastatic EMPD ( 11 ). Around 15–58% of EMPD patients overexpress HER2, which likely plays a crucial role in the development and progression of EMPD ( 17 ).…”

“…Dose-escalation and dose-expansion study had assessed the safety, tolerability, pharmacology and clinical activity of tislelizumab in patients with advanced solid tumors ( 10 ). Previous studies have reported low rates (10%) of PD-L1 expression in EMPD tumor cells ( 23 – 25 ), and checkpoint inhibitor blockade is recommended for patients with mismatch repair or microsatellite instability, or high mutational burden ( 11 ), that does not mean that there would be poor anti-tumor effect from checkpoint inhibitors in all EMPD cases. A prior study identified germline mismatch repair gene missense mutations in 8 of 20 EMPD tumors, with a proportion of cases exhibiting microsatellite instability (MSI), lending rationale for consideration of checkpoint inhibitor immunotherapy in such cases ( 26 ).…”

Case Report: Prolonged clinical benefit with sequential trastuzumab-containing treatments in a patient with advanced extramammary Paget disease of the groin

“…Skin punch biopsy revealed a proliferation of large round neoplastic elements spreading throughout the epidermis with dermal infiltration, coherent with EMPD. Immunoreactivity for cytokeratin 7 ( Figure 2A ) and EMA and negativity for cytokeratin 20 ( Figure 2B ) and Melan-A ruled out secondary pagetoid spread from urothelial or colorectal cancer and malignant melanoma ( 17 ). HER2 was highly expressed by immunohistochemistry (IHC) [score of 3+ according to CAP guidelines ( 29 )] ( Figure 2C ), and in situ hybridization (ISH) analysis revealed ERBB2 gene amplification ( Figure 2D ).…”

“…Treatment approaches for localized EMPD include broad surgical resection, radiotherapy, topical imiquimod, and photodynamic therapy; for patients with advanced (locally advanced or metastatic) EMPD, several chemotherapeutic agents, including 5-fluorouracil, taxanes, platinum salts, and vinca alkaloids, have shown moderate antitumor activity in published case series ( 14 – 17 ). More recently, anti-HER2 agents, alone or combined with chemotherapy, have shown promising antitumor activity in patients with HER2-overexpressing EMPD, as summarized in Table 1 ( 1 , 9 , 18 – 28 ).…”