Over the past 4 years, trichorhinophalangeal syndrome type 1 (TRPS1) has rapidly gained attention among practicing pathologists, with numerous studies emerging that both support and question its diagnostic utility. Initially regarded as a highly specific marker for tumors of mammary origin, TRPS1 is now recognized to have broader expression patterns, including in a variety of cutaneous neoplasms. This is likely due to embryologic parallels between breast tissue and skin adnexal structures, an overlap that was underappreciated in early investigations. Although TRPS1 lacks absolute specificity-even among cutaneous neoplasms-it can still offer meaningful diagnostic value when interpreted alongside conventional immunohistochemical markers and within the appropriate morphologic context. Noteworthy diagnostic applications include mammary Paget disease, primary extramammary Paget disease, rare adnexal neoplasms such as endocrine mucin-producing sweat gland carcinoma and primary cutaneous NUT adnexal carcinoma, and cutaneous metastases from breast carcinoma. In this review, we present the most comprehensive and up-to-date evaluation of the utility and limitations of TRPS1 immunohistochemistry in dermatopathology. Our aim is to deepen understanding of this emerging marker and provide practical guidance on its optimal integration with established immunohistochemical panels to enhance diagnostic accuracy in routine practice.

Defining the origin of metastatic cancer is crucial for establishing an optimal treatment strategy, especially when obtaining sufficient tissue from secondary malignancies is limited. While cytological examination is often used in this diagnostic setting, morphologic analysis alone often fails to differentiate metastases derived from the breast from other primaries. The hormone receptor, human epidermal growth factor receptor-2, gross cystic disease fluid protein 15, and mammaglobin immunohistochemistry are often used to diagnose metastatic breast cancer. However, their effectiveness decreases in estrogen receptor (ER)-negative breast cancers, including the triple-negative breast cancer (TNBC) subtype. We conducted a comprehensive evaluation of GATA-binding protein 3 (GATA-3), trichorhinophalangeal syndrome type 1 (TRPS-1), and Matrix Gla Protein (MGP) immunochemistry across 140 effusion cytology specimens with metastatic adenocarcinoma derived from various primaries, including the breast, colon, pancreaticobiliary, lung, tubo-ovarian, and stomach. The expression rates of these immunomarkers were significantly higher in metastatic cancers originating from the breast than other primaries. In TNBC, TRPS-1 (80.00%) and MGP (65.00%) exhibited higher positivity rates compared to GATA-3 (40.00%). Additionally, our data suggest that an immunohistochemical panel comprising MGP, GATA-3, and TRPS-1 significantly enhances the detection of metastatic breast cancer in effusion cytology specimens, including TNBC in particular. When considering dual-marker positivity, the diagnostic accuracy was found to be 89.29% across all breast cancer subtypes and 92.93% for TNBC. MGP appears to be a robust marker for identifying metastatic breast cancer in malignant effusions, especially TNBC. MGP notably enhances diagnostic accuracy when incorporated together with GATA-3 and TRPS-1 in an immunohistochemical panel.

Trichorhinophalangeal syndrome type 1; transcriptional repressor GATA binding 1 (TRPS1), a member of the GATA transcription factor family, functions primarily as a transcriptional repressor. TRPS1 is frequently utilised as a diagnostic marker for breast carcinoma, although its specificity is lower than previously believed. Moreover, TRPS1 is expressed in various solid tumours originating from the skin, salivary glands, soft tissues, prostate, urothelium, and female genital tract. The current study evaluated the diagnostic and prognostic significance of TRPS1 in 451 primary tubo-ovarian tumours. The cohort included 94 high-grade serous carcinomas (HGSCs), 81 low-grade serous carcinomas (LGSCs), 31 micropapillary serous borderline tumours (mSBTs), 92 clear cell carcinomas (CCCs), 52 endometrioid carcinomas (ECs), 31 mucinous carcinomas (MCs), and 70 mucinous borderline tumours (MBTs). Immunohistochemical analysis was performed using tissue microarrays following standardised protocols. Clinical data were analysed to determine the prognostic relevance of TRPS1 expression. TRPS1 expression was detected in 47% of HGSCs, 44% of ECs, 35% of CCCs, 19% of LGSCs, and 29% of mSBTs with complete negativity in MC/MBT. TRPS1-negative HGSC cases had higher recurrence rates than those with positive staining. Furthermore, TRPS1 expression significantly correlated with improved metastasis-free survival in HGSC cases. These findings suggest that TRPS1 may serve as an independent prognostic marker for HGSC. Despite varying expression rates across primary tubo-ovarian carcinomas, the routine use of TRPS1 in the differential diagnosis seems to be limited, ​as other robust immunohistochemical markers are available for distinguishing the individual subgroups. Further research is needed to clarify the specific functions and clinical implications of TRPS1 in tubo-ovarian cancer.

To analyse the diagnostic role of trefoil factor-1 and -3 (TFF1, TFF3), forkhead box protein A1 (FOXA1), carbonic anhydrase XII (CA XII) and trichorhinophalangeal syndrome type 1 (TRPS1) in serous effusions. The prognostic role of these markers in breast carcinoma was additionally studied. Protein expression by immunohistochemistry was analysed in 247 effusions, consisting of 60 breast carcinomas, 54 tubo-ovarian carcinomas, 47 mesotheliomas, 44 lung carcinomas, 20 uterine corpus and cervical carcinomas, 17 gastrointestinal carcinomas and 5 cancers of other origin. TFF1, TFF3, FOXA1, CA XII and TRPS1 expression was found in 67%, 70%, 88%, 82% and 83% of breast carcinomas, respectively. Expression of all markers was seen in some carcinomas of other origin, most commonly in GI metastases, but was least frequent for TRPS1. CA XII expression was additionally seen in mesotheliomas and reactive mesothelial cells. All 5 markers were significantly overexpressed in breast compared to tubo-ovarian carcinoma (all p < 0.001) and lung carcinoma (all p < 0.001 except for FOXA1, p = 0.023). TFF1 (p = 0.003), TFF3 (p = 0.008) and FOXA1 (p = 0.017) expression was significantly higher in receptor-positive compared to receptor-negative primary breast carcinomas. In survival analysis for 44 breast carcinoma patients with clinical data, TFF1 expression was associated with a trend for longer overall (p = 0.096) and disease-free (p = 0.06) survival. TFF1, TFF3, FOXA1, CA XII and TRPS1 are sensitive breast carcinoma markers, with FOXA1 performing best in terms of sensitivity and TRPS1 being the most specific. Whether the expression of these markers in breast carcinoma effusions is informative of survival merits further research.

Breast cancer, especially triple-negative breast cancer (TNBC), lacks sensitive and specific diagnostic markers that can reliably differentiate it from carcinomas of other origins. TRPS1 is a relatively new immunohistochemical (IHC) marker that has demonstrated higher sensitivity in breast cancer, including TNBC. However, with the increasing use of this marker, broader immunoreactivity has been observed. This study aims to evaluate the utility of TRPS1 for establishing carcinoma of mammary origin. We compared the diagnostic sensitivity and specificity of TRPS1 with that of other IHC markers (GATA3 and SOX10). In this retrospective study, we reviewed TRPS1 IHC performed at our center between 07/2022 and 06/2024, to evaluate the expression of TRPS1 in breast carcinoma (primary and distant metastasis) and in other malignancies. The sensitivity and specificity of TRPS1 in determining carcinoma of breast origin were compared with those of GATA3 and SOX10. The study cohort comprised 106 cases, including 17 cases at the primary site, and 89 samples of distant metastasis. After correlation with morphology, immunophenotype and molecular studies, 94 cases (88.7%) were characterized as breast primary (37.9% ER+/HER2neu-, 4.6% ER-/HER2neu+, 1.1% ER+/HER2neu+, 56.3% TNBC), whereas 12 (11.3%) were non-breast primary. The non-breast primary sites included lung, bladder, Mullerian, and gastrointestinal. The sensitivity and specificity of TRPS1 were 93.6% and 58.3%, respectively. Conversely, GATA3 demonstrated a sensitivity and specificity of 76.9% and 66.7%, respectively. SOX10 exhibited the lowest sensitivity at 47.9%, but with the highest specificity at 100%. There were three cases of metastatic breast carcinoma (sites: bladder, lung, and bone), where TRPS1 was the only positive marker, whereas GATA3 and SOX10 were negative. TRPS1 showed a higher positivity rate (92.0%) in TNBC compared to GATA3 (63.4%) and SOX10 (56.7%). TRPS1 expression was also observed in other tumor types, including carcinoma of Mullerian origin, bladder, and lung, limiting its utility in the differential diagnosis. Our study demonstrated a higher sensitivity of TRPS1 expression in establishing carcinoma of breast origin compared with GATA3 and SOX10, consistent with previous reported studies. However, the specificity of TRPS1 was lower than that of GATA3 and SOX10. These findings suggest that while TRPS1 can be used as a reliable marker for breast cancer, its expression in other tumor types should be carefully interpreted to avoid diagnostic pitfalls.