Abstract

Extramammary Paget disease (EMPD) predominantly manifests de novo as primary EMPD, with less than 30 % of cases associated with underlying internal malignancy (secondary EMPD). Differentiating primary from secondary EMPDs based solely on histopathology poses challenges, often necessitating supplementary screening, such as endoscopy or imaging studies, to definitively exclude underlying carcinomas like colonic adenocarcinoma. Recently, TRPS1 immunohistochemistry, initially identified as a sensitive and specific marker for carcinomas and mesenchymal tumors of mammary origin, has been proposed for EMPD. In this study, we conducted a systematic assessment of TRPS1 expression across 93 EMPD cases, comprising 82 primary EMPDs and 11 secondary EMPDs. Our aim was to assess the potential utility of TRPS1 as a marker to differentiate between primary and secondary EMPDs. Our findings revealed that 88 % (72/82) of primary EMPDs displayed TRPS1 expression, while secondary EMPDs consistently lacked TRPS1 expression (100 %; 11/11). Within the primary EMPD group, consistent TRPS1 immunoreactivity was observed in lesions originating outside the perianal region, such as the groin/inguinal area, axilla, and trunk. Interestingly, a majority (91 %; 10/11) of primary EMPDs originating in the perianal region exhibited an absence of TRPS1 expression. Upon excluding cases of perianal primary EMPDs, the sensitivity and specificity of TRPS1 for primary EMPDs reached 100 %. Our findings suggest that TRPS1 expression holds notable sensitivity and specificity for primary EMPDs, particularly when arising from non-perianal cutaneous sites. Hence, in suitable clinical contexts, TRPS1 immunohistochemistry may emerge as a promising and valuable tool for distinguishing primary and secondary EMPDs.

Introduction

Extramammary Paget disease (EMPD) is an uncommon form of Paget disease, typically originating in regions abundant in apocrine glands, notably the genital (vulva, scrotum) and perianal areas. In contrast to mammary Paget disease, which is closely linked to underlying breast carcinoma (ductal carcinoma in situ or invasive mammary carcinoma), EMPD often develops de novo (primary EMPD). Less than 30 % of EMPD cases are associated with underlying internal malignancies (secondary EMPD), such as colorectal adenocarcinoma or urothelial carcinoma [[1], [2], [3], [4]]. Paget cells in EMPD typically show immunoreactivity for CK7, Cam5.2, EMA, CEA, GATA3, and GCDFP-15, while lacking p63, CK5/6, and SOX10 expression. This distinctive immunoprofile usually aids in distinguishing EMPD from its morphological mimics like pagetoid squamous cell carcinoma in situ and melanoma in situ. However, these immunohistochemical markers do not effectively differentiate primary from secondary EMPDs. Additional immunohistochemical markers like CK20 and GCDFP-15 may offer insight, especially in perianal EMPDs. A CK7+/CK20-/GCDFP-15+ immunoprofile leans towards primary EMPD, whereas CK7+/CK20+/GCDFP-15- favors secondary EMPD [5]. Nevertheless, CK20 expression is not entirely exclusive to secondary EMPDs; around one-third of perianal primary EMPDs may exhibit CK20 immunoreactivity [5]. Consequently, supplementary screening via endoscopy or imaging is typically required to conclusively rule out underlying internal malignancies.

Recently, TRPS1 has emerged as a potential diagnostic marker for EMPD [6,7]. An initial study encompassing 19 primary EMPD cases found that 68 % (13/19) exhibited strong TRPS1 immunoreactivity [6]. Interestingly, cases lacking TRPS1 expression were consistently perianal in origin [6]. Subsequently, another study explored TRPS1 expression across 19 primary EMPD cases and 3 secondary EMPD cases [7]. In this study, all primary EMPDs (vulvar and scrotal) demonstrated TRPS1 positivity, while the 3 secondary EMPDs lacked TRPS1 expression. This suggests TRPS1 might be a sensitive and specific marker for primary EMPD [7]. However, the latter study's cohort was limited, with only 3 secondary EMPD cases, and lacked substantial primary perianal EMPD cases to confidently establish TRPS1's diagnostic utility in distinguishing primary from secondary EMPDs.

In this study, we evaluate TRPS1 expression in 93 EMPD cases, including 11 secondary EMPDs and 11 perianal primary EMPDs with confirmed absence of colorectal adenocarcinoma based on endoscopic and/or radiological findings. This aims to better ascertain TRPS1's sensitivity and specificity as a marker for primary EMPD.

Section snippets

Case selection

EMPD cases were retrieved from pathology archives after approval from Institutional Review Boards of the University of Texas MD Anderson Cancer Center (protocol 2022–0662) and Indiana University (protocol 20,351). A preliminary review of H&E-stained slides for potential cases preceded the retrieval of corresponding formalin-fixed, paraffin-embedded (FFPE) tissue blocks. This was done to ensure the adequacy of lesional cells for subsequent immunohistochemical analysis. Among the collection, …

Clinical characteristics of primary and secondary EMPDs

The study encompassed a total of 82 primary EMPD cases and 11 secondary EMPD cases (Table 1). The median age of patients with primary and secondary EMPDs displayed similarity (74 years in primary EMPD group vs. 71 years in secondary EMPD group). Gender distribution within the primary EMPD group showed no significant predilection towards males or females, whereas secondary EMPD cases exhibited a male predominance, with a male-to-female ratio of 1.8:1. In both cohorts, EMPDs were most frequently …

Discussion

While initially considered highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin [8,9], recent data challenges the notion that TRPS1 expression is exclusive to breast neoplasms. It has been observed in other cutaneous neoplasms, such as EMPD [6,7] and squamous cell carcinoma in situ [6], and even non-neoplastic reactive fibroblasts/myofibroblasts in the skin [10]. The presence of TRPS1 expression in EMPDs was first documented by Cho et al. [6], where strong TRPS1 …

Authors

Yi A. Liu, Katrina Collins, Phyu P. Aung, Priyadharsini Nagarajan, Jonathan L. Curry, Victor G. Prieto, Carlos A. Torres-Cabala, and Woo Cheal Cho.