Abstract
BackgroundPrimary Extra‐mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known.MethodsEighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy‐relevant protein biomarkers).ResultsMutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD‐L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a “high” tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable.ConclusionsEMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD‐L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations.
Highlights
Primary extra-mammary Paget's disease (EMPD) is a very rare, cutaneous adenocarcinoma of uncertain etiology commonly affecting anogenital or axillary regions
In contrast to MPD, we found overexpression and harbored pathogenic ERBB2 (HER2) gene amplification in a minority of cases, and a co-amplification with TOPO2 in a single case of vulvar disease
TOPO2α is the target for anthracyclins[22] chemotherapy and this biomarker was frequently altered in our study
Summary
Primary extra-mammary Paget's disease (EMPD) is a very rare, cutaneous adenocarcinoma of uncertain etiology commonly affecting anogenital or axillary regions. The Surveillance, Epidemiology and End Results (SEER) Registry reported an incidence of ~2200 cases in the United States over 40 years.[1] In contrast to the more common mammary Paget's disease, which is the manifestation of intra-epidermal dissemination of an underlying invasive or in situ breast carcinoma, or secondary extra-mammary pagetoid spread of adenocarcinomas from various internal organs, primary cutaneous EMPD lacks an underlying malignancy.[2] Primary EMPD is a slowly progressive disease and is usually diagnosed while at the in situ (intra-epidermal) stage Following dermal invasion, it metastasizes to regional lymph nodes and potentially other distant sites.[3] The postsurgical (local) recurrence rate in EMPD is 20%-40% and metastatic EMPD has a poor survival rate.[3]. We compared comprehensive molecular-genetic profiles of a cohort of primary EMPD to primary mammary Paget's disease (MPD) to detect common and distinguishing tumor characteristics, providing additional supportive evidence for optimal therapy approaches.[6]
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