Trichorhinophalangeal Syndrome Type 1 Research Articles

TRPS1 expression in MPNST is correlated with PRC2 inactivation and loss of H3K27me3

Initially described as a highly specific immunohistochemical marker for carcinomas of mammary origin, trichorhinophalangeal syndrome type 1 (TRPS1) has subsequently been detected in a variety of other non-mammary tumors. In this study, we examined the immunohistochemical expression of TRPS1 in 114 peripheral nerve sheath tumors, including 43 malignant peripheral nerve sheath tumors (MPNSTs), 58 schwannomas, including 9 cellular neurofibromas, and 13 neurofibromas, including 1 atypical neurofibroma. Notably, TRPS1 was expressed in 49% of MPNSTs and was absent in all schwannomas and neurofibromas. All MPNSTs showed TRPS1 labeling in >50% of nuclei, with 95% of cases demonstrating diffuse labeling. Most cases (67%) showed weak TRPS1 immunoreactivity, while a smaller subset showed moderate (24%) or strong (9%) intensity staining. Analysis of publicly available gene expression datasets revealed higher levels of TRPS1 mRNA in MPNSTs with PRC2 inactivation. In keeping with this finding, TRPS1 expression was more commonly observed in MPNSTs with loss of H3K27me3, suggesting a potential relationship between TRPS1 and the PRC2 complex. This study further broadens the spectrum of TRPS1-expressing tumors to include MPNST.

TRPS1 function beyond breast: A retrospective immunohistochemical study on non-breast cytology specimens.

Trichorhinophalangeal syndrome type 1 (TRPS1) has emerged as a reliable immunohistochemistry (IHC) marker for identifying breast origin in metastatic carcinomas. This study investigates the utility of TRPS1 IHC in non-breast cytology specimens. A retrospective search of our pathology database for the year 2021 identified fluids (pleural and peritoneal) and liver, lung and bone fine needle aspirations (FNAs) with surgical follow-up confirming non-breast metastatic carcinomas. Cell blocks from cases with sufficient neoplastic cells underwent immunostaining using a rabbit polyclonal antibody against human TRPS1. Cases lacking tumor on deeper levels after the original work-up were excluded from the study. Two pathologists independently interpreted the TRPS1 staining. Of 136 cases assessed, 31 (22.79%) exhibited positive TRPS1 staining, while 105 (77.21%) were nonreactive. Positivity rates were observed in tumors of Mullerian cell origin, gastrointestinal tract (GIT), and lung origin at 28.85%, 25%, and 21.57%, respectively. Of the tumors of Mullerian cell origin 10 (66.67%) were serous carcinomas, 4 (26.67%) were endometrioid carcinomas, and one (6.67%) was a clear cell carcinoma. Lung tumors comprised seven (63.64%) squamous cell carcinomas and four (36.36%) adenocarcinomas, while the gastrointestinal tumors consisted of 14 (80%) adenocarcinomas and one (20%) squamous cell carcinoma. Although recognized as a sensitive marker for mammary carcinomas, TRPS1 immunostaining was also detected in Mullerian, lung, and GIT carcinomas. This highlights the significance of being cautious when depending solely on TRPS1 immunostaining to distinguish metastatic breast tumors.

Diagnostic utility and sensitivities of matrix Gla protein (MGP), TRPS1 and GATA3 in breast cancer: focusing on metastatic breast cancer, invasive breast carcinoma with special features, and salivary gland-type tumours

Matrix Gla protein (MGP) and trichorhinophalangeal syndrome type 1 (TRPS1) have recently emerged as novel breast-specific immunohistochemical (IHC) markers, particularly for triple-negative breast cancer (TNBC) and metaplastic carcinoma. The present study aimed to validate and compare the expression of MGP, TRPS1 and GATA binding protein 3 (GATA3) in metastatic breast carcinoma (MBC), invasive breast carcinoma (IBC) with special features, including special types of invasive breast carcinoma (IBC-STs) and invasive breast carcinoma of no special type with unique features, and mammary and non-mammary salivary gland-type tumours (SGTs). Among all enrolled cases, MGP, TRPS1 and GATA3 had comparable high positivity for ER/PR-positive (p=0.148) and HER2-positive (p=0.310) breast carcinoma (BC), while GATA3 positivity was significantly lower in TNBC (p<0.001). Similarly, the positive rates of MGP and TRPS1 in MBCs (99.4%), were higher than in GATA3 (90.9%, p<0.001). Among the IBC-STs, 98.4% of invasive lobular carcinomas (ILCs) were positive for all three markers. Among neuroendocrine tumours (NTs), all cases were positive for TRPS1 and GATA3, while MGP positivity was relatively low (81.8%, p=0.313). In the neuroendocrine carcinoma (NC) subgroup, all cases were positive for GATA3 and MGP, while one case was negative for TRPS1. All carcinomas with apocrine differentiation (APOs) were positive for GATA3 and MGP, while only 60% of the cases demonstrated moderate staining for TRPS1. Among mammary SGTs, MGP demonstrated the highest positivity (100%), followed by TRPS1 (96.0%) and GATA3 (72.0%). Positive staining for these markers was also frequently observed in non-mammary SGTs. Our findings further validate thehigh sensitivity of MGP and TRPS1 in MBCs, IBC-STs, andbreast SGTs. However, none of these markers arecapable of distinguishing between mammary and non-mammary SGTs.

TRPS1 expression in non-melanocytic cutaneous neoplasms: an immunohistochemical analysis of 200 cases.

Although trichorhinophalangeal syndrome type 1 (TRPS1) was initially thought to be highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin, more recent data suggest its expression is not limited to breast neoplasms but also can be seen in other cutaneous neoplasms, such as extramammary Paget disease and squamous cell carcinoma (SCC) in situ. Two-hundred cases of non-melanocytic cutaneous neoplasm, including basal cell carcinomas (BCCs) (n = 41), SCCs (n = 35), Merkel cell carcinomas (MCCs) (n = 25), and adnexal neoplasms (n = 99), were tested for TRPS1 expression using a monoclonal anti- TRPS1 rabbit anti-human antibody. TRPS1 expression was present in almost all cases of SCC (94%), with a median H-score of 200, while it was either absent or only focally present in most BCCs (90%), with a median H-score of 5. The difference between BCCs and SCCs in H-score was significant (p < .001). All MCCs (100%) lacked TRPS1 expression. TRPS1 expression was frequently seen in most adnexal neoplasms, benign and malignant, in variable intensity and proportion but was consistently absent in apocrine carcinomas. All endocrine mucin-producing sweat gland carcinomas (EMPSGCs) (100%, 6/6) showed diffuse and strong TRPS1 immunoreactivity, with a median H-score of 300, which was significantly different (p < .001) than that of BCCs. Our study shows that TRPS1 may be an effective discriminatory marker for BCCs and SCCs. It also has a role in distinguishing BCCs from EMPSGCs.

Trichorhinophalangeal Syndrome Type 1 Immunohistochemical Expression in Carcinomas of Gynecologic Origin.

Trichorhinophalangeal syndrome type 1 (TRPS1) is a new reportedly sensitive and specific immunohistochemical marker for carcinomas of breast origin, including triple-negative (estrogen receptor, progesterone receptor, and HER2) tumors. In our practice, we have observed a subset of cases of nonmammary carcinomas that are positive for TRPS1, with higher frequency in cytology effusion samples with metastatic gynecologic malignancies. This study aimed to evaluate the expression of TRPS1 in a large tissue cohort of Müllerian carcinomas. We retrospectively retrieved 105 cases of formalin-fixed paraffin-embedded gynecologic tumors from our surgical pathology archives. Cases corresponded to tumors of tubo-ovarian (17 high-grade serous carcinomas, 3 low-grade serous carcinomas, 2 clear cell carcinomas, and 8 endometrioid adenocarcinomas), endometrial (25 endometrioid adenocarcinomas, 8 serous carcinomas, 6 clear cell carcinomas, 12 carcinosarcomas, 1 dedifferentiated carcinoma, and 1 mesonephric-like adenocarcinoma), cervical (6 human papillomavirus [HPV]-associated squamous cell carcinomas [SCCs], 11 HPV-associated endocervical adenocarcinomas, and 2 HPV-independent gastric-type endocervical adenocarcinomas), and vulvar (2 HPV-independent SCCs and 1 HPV-associated SCC) origins. Immunohistochemistry for TRPS1 was performed in whole tissue sections and assessed for positivity (≥5% of nuclear labeling), distribution (focal: 5% to 49%, diffuse: 50% to 100%), and intensity (1+, 2+, 3+) in tumor cells. Positive TRPS1 staining was observed in 51.4% (54/105) of cases. Most tumors (64.8%) demonstrated diffuse labeling, while focal in 35.2%. Among positive cases, the intensity was predominantly 1+ (57.4%), followed by 2+ (33.3%) and 3+ (9.2%). Tumors with a high percentage of positivity overall consisted of tubo-ovarian (70%) and endometrial carcinomas (58.4%). TRPS1 immunostain is often expressed in gynecologic carcinomas. Awareness of this phenomenon is crucial when evaluating challenging cases in which the differential diagnosis includes a malignancy of breast origin, to avoid misclassification of the primary site.

TRPS1 expression in primary and metastatic prostatic adenocarcinoma, muscle invasive bladder urothelial carcinoma, and breast carcinoma: Is TRPS1 truly specific and sensitive for a breast primary?

Trichorhinophalangeal syndrome type 1 (TRPS1) has been reported to be a sensitive and specific immunohistochemical (IHC) marker for breast carcinomas, especially when determining primary site of origin. However, there is limited data on TRPS1 expression in prostate and bladder cancers.A two-phase study was performed with 1) an exploratory cohort analyzing TRPS1 gene alterations in prostate, bladder, and breast carcinoma and TPRS1 mRNA expression data in prostate and bladder carcinoma; and 2) TRPS1 and GATA3 IHC in a confirmatory cohort in prostate, bladder, and breast carcinoma samples.Gene alterations were identified in a subset of breast, bladder, and prostate carcinomas and mRNA was consistently detected. In the IHC cohort, 183/210 (87.1 %) of breast, 22/69 (31.9 %) of prostate, and 20/73 (27.4 %) of urothelial carcinomas showed staining with TRPS1. Intermediate to high expression of TRPS1 was observed in 173/210 (82.8 %) of breast, 17/69 (24.6 %) of prostate, and 15/73 (20.5 %) of urothelial carcinomas. Furthermore, in prostate cancer, 26.9 % of pelvic lymph node metastases and 50 % in sites of distant metastases showed expression. Increased TRPS1 mRNA expression (p = 0.032) and IHC expression (p = 0.040) correlated with worse overall survival in bladder cancer. By comparison, GATA3 IHC stained 136/210 (64.8 %) of breast, 0/69 (0 %) of prostate, and 63/73 (93 %) of bladder carcinomas. Intermediate to high expression of GATA3 was seen in 131/210 (62.4 %) of breast and 63/73 (93 %) of bladder carcinomas.This study shows there is significant staining of TRPS1 in bladder and prostate cancers. As a result, comprehensive studies are needed to establish the true specificity of TRPS1 IHC stain across various tumor types before its widespread clinical adoption.

Mucinous cystadenocarcinoma of the breast harbours TRPS1 expressions and PIK3CA alterations.

Breast mucinous cystadenocarcinoma (BMCA) is a rare tumour recently recognised as a distinct entity by the World Health Organisation Tumour Classification Series. BMCA is a triple-negative tumour that lacks specific immunohistochemical markers; therefore, distinguishing it from mimickers such as ovarian and pancreatic cystadenocarcinomas requires careful clinicopathological correlation. Due to its rarity, little is known about the molecular alterations that underlie BMCA. In this study, we used immunohistochemical staining methods to investigate TRPS1 (trichorhinophalangeal syndrome type 1) expression in BMCA and compare it to expression in ovarian and pancreatic mucinous cystadenocarcinomas. We also collected tumour samples from three BMCA patients for molecular analysis by MALDI-TOF mass spectrometry, real-time polymerase chain reaction, whole exome sequencing and fluorescence in-situ hybridisation. TRPS1 immunoreactivity was found only in BMCA tumour cells and not in the ovarian and pancreatic counterparts. One of the three BMCA tumours also showed a PIK3CA hot-spot mutation, which was confirmed by whole genome next-generation sequencing (NGS). No KRAS, NRAS, BRAF or AKT mutations were found. To our knowledge, this is the first demonstration of TRPS1 expression in BMCA patients and the first identification of a PIK3CA hotspot mutation in these tumours. These findings provide insights into the molecular mechanisms underlying BMCA tumorigenesis and suggest a potential drug target for this rare and poorly understood cancer.

Diagnostic Utility of Trichorhinophalangeal Syndrome Type 1 (TRPS1) immunostain in breast carcinoma compared to GATA3

Diagnostic Utility of Trichorhinophalangeal Syndrome Type 1 (TRPS1) immunostain in breast carcinoma compared to GATA3

Trichorhinophalangeal Syndrome Type 1 Is a Highly Sensitive and Specific Marker for Diagnosing Triple-Negative Breast Carcinomas on Cytologic Samples.

Definitive diagnosis of metastatic triple-negative breast carcinoma (TNBC) is challenging on cytologic samples. Recent studies demonstrated that trichorhinophalangeal syndrome type 1 (TRPS1) is a highly sensitive and specific marker for diagnosing breast carcinomas, including TNBC, on surgical specimens. To evaluate TRPS1 expression in TNBCs on cytologic samples and a large series of nonbreast tumors on tissue microarray sections. Immunohistochemical (IHC) analysis of TRPS1 and GATA-binding protein 3 (GATA3) was performed on 35 TNBC cases on surgical specimens, and 29 consecutive TNBC cases on cytologic specimens. IHC analysis of TRPS1 expression was also performed on 1079 nonbreast tumors on tissue microarray sections. Of the surgical specimens, 35 of 35 TNBC cases (100%) were positive for TRPS1, all with diffuse positivity, whereas 27 of 35 (77%) were positive for GATA3, with diffuse positivity in 7 cases (26%). Of the cytologic samples, 27 of 29 TNBC cases (93%) were positive for TRPS1, with diffuse positivity in 20 cases (74%), whereas 12 of 29 (41%) were positive for GATA3, with diffuse positivity in 2 cases (17%). Of the nonbreast malignant tumors, TRPS1 expression was seen in 9.4% (3 of 32) of melanomas, 10.7% (3 of 28) of small cell carcinomas of the bladder, and 9.7% (4 of 41) of ovarian serous carcinomas. Our data confirm that TRPS1 is a highly sensitive and specific marker for diagnosing TNBC cases on surgical specimens as reported in the literature. In addition, these data demonstrate that TRPS1 is a much more sensitive marker than GATA3 in detecting metastatic TNBC cases on cytologic samples. Therefore, inclusion of TRPS1 in the diagnostic IHC panel is recommended when a metastatic TNBC is suspected.

Trichorhinophalangeal syndrome type 1 (TRPS1) expression in male breast carcinoma

Currently, there is a paucity of highly specific and sensitive markers to identify breast carcinoma in male patients. Immunohistochemical stains commonly used for unmasking primary breast carcinomas include estrogen receptor (ER) and GATA3. However, these markers are commonly expressed in carcinomas originating from other organ systems and can be reduced in breast carcinomas with higher histologic grades. Androgen receptor (AR) may be used to highlight primary male breast cancer, but this marker can also be expressed in other carcinomas. We evaluated TRPS1, a highly sensitive and specific marker for female breast carcinoma, in cases of male breast carcinoma. Through an institutional database search, we identified 72 cases of primary invasive breast carcinoma in male patients. Among ER/progesterone receptor (PR)-positive cancers, 97% showed intermediate or high positivity for both TRPS1 and GATA3. Among HER2-positive cancers, 100% showed intermediate or high positivity for TRPS1 and GATA3. One case of triple-negative breast cancer was collected, showing high positivity for TRPS1 and negativity for GATA3. AR staining was non-specific and heterogeneous: 76% showed high positivity, but the remaining 24% showed low or intermediate positivity. Additionally, among 29 cases of metastatic carcinoma to male breast tissue, 93% were negative for TRPS1, and the remaining 2 cases (7%), which were carcinomas from salivary gland primary tumors, were intermediate positive. TRPS1 is a sensitive and specific marker in the unmasking of male primary invasive breast carcinoma across different subtypes. Additionally, TRPS1 is not expressed in metastatic carcinomas of multiple primaries, with the exception of salivary gland primaries.

TRPS1: A Marker of Follicular Differentiation.

The trichorhinophalangeal syndrome type 1 (TRPS1) immunohistochemical (IHC) stain has increased in use in recent years as a marker for breast carcinomas. The TRPS1 gene is involved in various tissues, including the growth and differentiation of hair follicles. This article seeks to evaluate the IHC expression of TRPS1 in cutaneous neoplasms with follicular differentiation, such as trichoblastoma (TB), trichoepithelioma (TE), and basal cell carcinoma (BCC). IHC studies were performed on 13 TBs, 15 TEs, and 15 BCCs with an antibody against TRPS1. The study found a variable staining expression of TRPS1 in the tumor nests of TB, TE, and BCC. BCCs were distinct in that none of the BCCs demonstrated intermediate or high positivity, while TBs and TEs showed intermediate-to-high positivity in 5/13 (38%) and 3/15 (20%) of cases, respectively. We observed a distinct staining pattern among the mesenchymal cells of TB and TE. We found that TRPS1 highlighted perifollicular mesenchymal cells adjacent to the nests of TB and TE tumor cells. This staining pattern was absent in BCCs, where only scattered stromal cells were positive for TRPS1. Papillary mesenchymal bodies were also highlighted by TRPS1 in TB and TE. TRPS1 stained various parts of the normal hair follicle, including the nuclei of cells in the germinal matrix, outer root sheaths, and hair papillae. TRPS1 may be a useful IHC marker for follicular differentiation.

TRPS1 outperforms GATA3 in pleural effusions with metastatic breast carcinoma versus mesothelioma.

In evaluating malignant pleural fluid cytology, metastatic adenocarcinomas and mesotheliomas are often differential diagnoses. GATA binding protein 3 (GATA3) has historically been used to confirm metastatic breast carcinomas; however, GATA3 has low specificity if mesothelioma is included in differential diagnoses. Trichorhinophalangeal syndrome type 1 (TRPS1) protein is expressed in all types of breast carcinomas, with reported high specificity and sensitivity. We investigated the performance of TRPS1 immunohistochemistry (IHC) and compared it to GATA3 in pleural fluids diagnosed with metastatic breast carcinoma and mesothelioma. Thirty-six consecutive ThinPrep pleural fluids and 4 pleural fine needle aspirations (FNAs) with diagnoses of metastatic breast carcinoma (21) and mesothelioma (19) were retrieved, and IHC with TRPS1 and GATA3 was performed on all. Immunoreactivity scores for TRPS1 were calculated by multiplying percentage of immunoreactive cells by staining intensity. Immunoreactivity scores were negative if 0 or 1, low positive if 2, intermediate positive if 3 or 4, or high positive if 6 or 9. Nuclear immunoreactivity of ≥10% with at least moderate intensity was judged GATA3 positive. GATA3 showed immunoreactivity in all metastatic breast carcinomas and 84% of mesotheliomas. TRPS1 was immunoreactive in all breast carcinoma cases (18 with a score of 9 and 3 with a score of 6). TRPS1 showed low positivity in 5% of mesothelioma cases with all other cases being negative. When cytomorphologic differential diagnoses of mesothelioma exist, TRPS1 is a more specific marker than GATA3 for confirmation of metastatic breast carcinoma in pleural fluid cytology.

Abstract 4607: TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways

Abstract Background. Triple-negative breast cancer (TNBC), the most difficult subtype to treat, is defined as estrogen receptor, HER2, and progesterone receptor negative. TNBC constitutes 10-20% of all breast cancer and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 years and almost all die from their disease despite adjuvant chemotherapy. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. Clinical trials with anti-angiogenic drugs showed to be inadequate, with moderate response rates and insignificant survival gains for patients. To understand the genetic forces involved in TNBC, we performed a transposon mutagenesis screen in Pten mutant mice that identified several candidate trunk drivers and progression genes. A major finding of our screen was the discovery and functional validation of, Trichorhinophalangeal syndrome type 1 (TRPS1), a GATA-like transcription factor, which functions as a transcriptional repressor or activator, depending on cell type, stage of development, or pathological conditions. Based on this data, we explored the role of TRPS1 in angiogenesis. Methods and Results. Tube formation and sprouting assays were performed using overexpression and inactivation of TRPS1 in MDA-MD-231 and HCC70 cells, respectively. Interestingly, inactivation of TRPS1 expression accelerates tube formation structures compared to the vector control as well as cell branching in the sprouting assay. Overexpression of TRPS1 prevents tubing and branching formation in vitro assays. Moreover, immunohistochemistry staining of CD31 detected a reduced number of blood vessels in MDA-MB-231 tumor xenografts overexpressing TRPS1, and an increase of angiogenic vasculature in HCC70 TRPS1-shRNA tumor xenografts. In vitro and in vivo assays demonstrate the role of TRPS1 in tumor angiogenesis. Furthermore, human ChIP qPCR angiogenesis array identified 10 top candidate genes potentially regulated by TRPS1 transcription factor. Of these candidates, JAG1 and TYMP showed to have a higher fold enrichment compared to other angiogenic related genes. Finally, we validated its direct functional binding by using luciferase reporter assay, such demonstrated that TRPS1 is a direct transcriptional regulator of JAG1 and TYMP. Conclusion. TRPS1 is a tumor suppressor involved in the mechanisms regulating tumor angiogenesis by repressing the expression of JAG1 and TYMP genes in TNBC. Citation Format: Liliana Guzman. TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4607.

TRPS1 expression in cytokeratin 5 expressing triple negative breast cancers, its value as a marker of breast origin

The lack of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 expression in breast cancer (BC) is the basis for the categorization of the tumour as triple negative breast carcinoma (TNBC). The majority of TNBCs are aggressive tumours with common metastases and decreased expression of markers that could help in identifying the metastatic lesion as of mammary origin. Breast markers, such as gross cystic disease fluid protein-15 (GCDPF-15), GATA binding protein 3 (GATA3), mammaglobin (MGB) and SOX10, are not uniquely specific to BC. Our aim was to evaluate trichorhinophalangeal syndrome type 1 (TRPS1) protein as a breast marker in a series of cytokeratin-5-expressing TNBC, mostly corresponding to basal-like TNBCs, previously characterized for the expression of other breast markers. One hundred seventeen TNBCs in tissue microarrays were immunostained for TRPS1. The cut-off for positivity was ≥ 10%. The reproducibility of this classification was also assessed. TRPS1 positivity was detected in 92/117 (79%) cases, and this exceeded the expression of previously tested markers like SOX10 82 (70%), GATA3 11 (9%), MGB 10 (9%) and GCDFP-15 7 (6%). Of the 25 TRPS1-negative cases, 11 were positive with SOX10, whereas 5 to 6 dual negatives displayed positivity for the other makers. The evaluation showed substantial agreement. Of the five markers compared, TRPS1 seems the most sensitive marker for the mammary origin of CK5-expressing TNBCs. Cases that are negative are most often labelled with SOX10, and the remainder may still demonstrate positivity for any of the 3 other markers. TRPS1 has a place in breast marker panels.

Utility of TRPS1 in Malignant Effusion Cytology

Introduction: Identifying metastatic breast carcinoma (mBC) in malignant effusion cytology (MEC) specimens is critical, as this will determine the patient’s prognosis and therapeutic management. Overlapping cytomorphologic features of breast carcinoma (BC) with other neoplastic entities makes the use of sensitive and specific markers highly desirable. Recent studies have reported trichorhinophalangeal syndrome type 1 (TRPS1) as a sensitive and specific marker for primary BC and mBC. We aimed to investigate TRPS1 expression in MEC of mBC and its most common diagnostic mimickers. Materials and Methods: A retrospective search from the pathology archives identified 82 MEC. TRPS1 expression in mBC was analyzed, and the results were compared to those in metastatic carcinoma of Müllerian origin (mMC) and metastatic pulmonary adenocarcinoma (mPAC). TRPS1 immunoperoxidase was performed on cytospin or cell block preparations, and p < 0.05 was considered significant. Results: Nuclear expression for TRPS1 was evaluated and scored as positive (≥1% of tumor cells) or negative. Nuclear TRPS1 expression was seen in 100% (30/30) mBC, 72% (18/25) mMC, and 7% (2/27) mPAC. This resulted in sensitivity, specificity, positive predictive value, and negative predictive values of 100%, 61%, 60%, and 100%, respectively. Conclusion: TRPS1 is a sensitive marker for mBC and can be reliably performed on cytology specimens. TRPS1 expression was also identified in a significant proportion of mMC, creating a potential diagnostic pitfall. Therefore, caution should be exercised when evaluating MEC of mBC with TRPS1. Consequently, a combination of immunoperoxidase panels should be employed in this setting.

Expanding the clinical and molecular features of trichorhino- phalangeal syndrome with a novel variant.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare, autosomal dominant disorder characterized by typical craniofacial features, ectodermal and skeletal findings. TRPS type 1 (TRPS1) is caused by pathogenic variations in the TRPS1 gene, which relates to the vast majority of cases. TRPS type 2 (TRPS2) is a contiguous gene deletion syndrome involving loss of functional copies of the TRPS1, RAD21, and EXT1. Herein, we reported the clinical and genetic spectrum of seven TRPS patients with a novel variant. We also reviewed the musculoskeletal and radiological findings in the literature. Seven Turkish patients (three female, four male) from five unrelated families aged between 7 to 48 years were evaluated. The clinical diagnosis was confirmed by either molecular karyotyping or TRPS1 sequencing analysis via next-generation sequencing. Both TRPS1 and TRPS2 patients had some common distinctive facial features and skeletal findings. All patients had a bulbous nose with hypoplastic alae nasi, brachydactyly, short metacarpals and phalanges in variable stages. Low bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. Skeletal X-ray imaging revealed cone-shaped epiphysis of the phalanges in all, and multiple exostoses were present in three patients. Cerebral hamartoma, menometrorrhagia and long bone cysts were among the new/rare conditions. Three pathogenic variants in TRPS1 were identified in four patients from three families, including a frameshift (c.2445dup, p.Ser816GlufsTer28), one missense (c.2762G > A), and a novel splice site variant (c.2700+3A > G). We also reported a familial inheritance in TRPS2 which is known to be very rare. Our study contributes to the clinical and genetic spectrum of patients with TRPS while also providing a review by comparing with previous cohort studies.

The diagnostic utility of trichorhinophalangeal syndrome type 1 immunohistochemistry for metastatic breast carcinoma in effusion cytology specimens.

Trichorhinophalangeal syndrome type 1 (TRPS1) is a novel immunohistochemical marker with excellent performance in distinguishing breast carcinoma from other cancers in surgical specimens. The aim of this study was to evaluate the diagnostic utility of TRPS1 compared with GATA3 for metastatic breast carcinoma in effusion cytology specimens. In total, 91 cell blocks of malignant effusion specimens, including 47 metastatic breast carcinomas (nine triple-negative breast carcinomas [TNBCs] and 38 non-TNBCs) and 44 nonmammary malignancies, were selected for TRPS1 and GATA3 immunohistochemistry. Modified H scores ≥ 200 were considered positive staining. The positive rate of TRPS1 was similar between TNBC and non-TNBC (77.8% vs 73.3%, p=.802), whereas the positive rate of GATA3 was lower in TNBC than in non-TNBC (66.7% vs 89.5%, p=.087). The positive rate of TRPS1 was significantly higher in breast carcinoma than in urothelial carcinoma (74.5% vs 0%, p<.001), whereas the positive rate of GATA3 showed no difference between these two (85.1% vs 85.7%, p=.956). Notably, diffuse and strong aberrant expression of TRPS1 was observed in one lung adenocarcinoma and one serous adenocarcinoma in this series. The overall sensitivity, specificity, positive predictive value, and negative predictive value of TRPS1 immunohistochemistry for breast carcinoma were 74.5%, 95.5%, 94.6%, and 77.8%, respectively. TRPS1 is a sensitive and specific marker for metastatic breast cancer in serous effusion cell-block specimens. It shows superior sensitivity and specificity compared with GATA3, especially in the TNBC setting and for excluding urothelial carcinoma.

Utility of TRPS-1 immunohistochemistry in diagnosis of metastatic breast carcinoma in cytology specimens

At present, GATA binding protein 3 (GATA-3) is the most frequently used diagnostic immunohistochemical (IHC) marker for breast carcinoma (BC). However, it is not specific and has very low sensitivity for triple-negative BC (TNBC). SRY-box transcription factor 10 (SOX-10) and trichorhinophalangeal syndrome type 1 (TRPS-1) have been suggested for inclusion in the diagnostic workup of TNBC. TRPS-1 has not been established in cytology specimens as a diagnostic IHC marker for metastatic BC (MBC). Hence, in the present study we evaluated the utility of TRPS-1 in diagnosing MBC in cytology specimens. MBC cases diagnosed on cytology specimens from January to October 2020 were included in the present study. Only cases with hormonal status available and ≥20 tumor cells on cell blocks were included in the study. The cell blocks were assessed for TRPS-1, GATA-3, and SOX-10 IHC marker positivity (intensity and percentage of tumor cells). The results were correlated with the specimen type (fine needle aspiration [FNA] versus body fluid) and various BC prognostic subgroups. We analyzed 61 cases, including 33 body fluid and 28 FNA (13 lymph node, 10 bone, 2 liver, 2 soft tissue, and 1 lung) specimens. TRPS-1 had 97.2% positivity in ER/PR+ (estrogen receptor/progesterone receptor-positive) MBC compared with GATA-3, which had 100% positivity in the same group. TRPS-1 showed high positivity in 35 of 37 cases (94.6%) and intermediate positivity in 1 (2.6%) and was negative/low positive in 1 case (2.7%). In contrast, GATA-3 showed high positivity for all 37 cases (100%). SOX-10 showed positivity in only 1 of 37 cases (2.7%), with intermediate positivity. In the HER2+ (human epidermal growth factor receptor 2-positive) group, TRPS-1 showed high positivity in 5 of 7 cases (71.4%), intermediate positivity in 1 case (14.3%), and negativity in 1 case (14.3%). However, GATA-3 showed high positivity in 6 of 7 cases (85.7%) and negative/low positivity in 1 case (14.3%). SOX-10 was negative in all 7 cases. In TNBC, TRPS-1 showed high positivity in 16 of 17 cases (94%) and intermediate positivity in 1(5.9%), and GATA-3 showed high positivity in 9 (53%), intermediate positivity in 2 (11.8%), and low positive/negative in 6 of the 17 cases (35.3%). TRPS-1 expression was significantly higher than GATA-3 expression for the number of positive cases (P = 0.07), mean percentage of positive tumor cells (P=0.005), and intensity of reactivity (P = 0.005). SOX-10 expression was present in only 5 of 17 cases (29%), with a mean percentage of positivity in the tumor cells of 26.5% and intensity of 0.8. No differences were found in the IHC results between the different specimen types (FNA versus fluid) in any group. TRPS-1 is a highly sensitive new diagnostic IHC marker for breast carcinoma, with a similar positivity rate in ER/PR+ and HER2+ BC compared with GATA-3 and a higher positivity rate than GATA-3 and SOX-10 in TNBC in cytology specimens. In particular, when only a few clusters of tumor cells are present on the cell block, TRPS-1 can be highly useful, because its mean percentage of positive tumor cells and intensity are higher than those of other IHC markers.

A 15-Year-Old Girl with Trichorhinophalangeal Syndrome Type 1 with Non-ossifying Fibroma in Femur: A Case Report

Introduction: Trichorhinophalangeal syndrome (TRPS) is a sporadic autosomal dominant disorder with approximately 200 reported cases worldwide. We aimed to report a 15-year-old girl with TRPS type 1 (TRPS1) and the second reported case with a rare non-ossifying fibroma (NOF) in the distal part of her left femur. Case Presentation: We introduce a 15-year-old girl who presented to the outpatient rheumatology clinic at 17 Shahrivar Children's Hospital, Rasht, Iran, with the chief complaint of osteoarticular pain and bone deformities. She had sparse hair, a recession of the fronto-temporal hairline, and unusually thick eyebrows at the medial and abnormal sparseness of the lateral margins. Physical examination of the limbs revealed short fingers and toes with proximal interphalangeal (PIP) ulnar deviation of the second and third fingers in both hands. Shortness of the fourth fingers, especially in the right hand, and the swelling of the PIP joints of both hands were prominent. Genetic analysis showed deletion mutation in the TRPS1 gene in chromosome 8q24 compatible with TRPS1. Conclusions: Several symptoms and signs, including distinctive craniofacial features and ectodermal and skeletal abnormalities, are used for proper TRPS diagnosis. A correct and on-time diagnosis is essential to perform supportive care for the patient to prevent morbidities. Bone lesions, such as NOF1, can also be presented in TRPS1 patients and may be correlated with TRPS1 mutation. Further investigations are required on the association of the TRPS gene with NOF bone lesions.

Evaluation of TRPS1 Expression in Pleural Effusion Cytology Specimens With Metastatic Breast Carcinoma.

Recent studies have shown that trichorhinophalangeal syndrome type 1 (TRPS1) is a sensitive and specific marker that shows positive staining in breast carcinoma. We conducted this study to evaluate the role of TRPS1 immunohistochemistry (IHC) in differentiating breast primary vs tumors from other primary sites in malignant pleural effusion cytology specimens (MPECSs). We selected 61 MPECS cases with cell block material available to analyze TRPS1 IHC staining. Of these 61 cases, 38 cases were metastatic carcinoma (MC) from a breast primary. We primarily selected MC cases confirmed as breast origin based on GATA binding protein 3 IHC positivity, except in two of the cases. The remaining 23 MPECS cases were from various primary sites, including urothelial (n = 6), Müllerian (n = 6), lung adenocarcinoma (n = 6), malignant melanoma (MM; n = 3), and squamous cell carcinoma (SqCC; n = 2). TRPS1 expression was observed in 35 (92%) of 38 MCs of breast origin. The staining intensity was variable, with 18 (47%) cases showing strong nuclear expression. In comparison, no TRPS1 expression was seen in any cases of urothelial carcinoma, MM, and SqCC. However, four of six Müllerian MC cases demonstrated TRPS1 expression. TRPS1 is a new marker that can be used in an IHC panel to investigate breast origin in MPECS.