Progesterone Receptor Staining Research Articles

Spectrum of Ductal Carcinoma In Situ (DCIS) Lesions of the Breast: From Morphology to Molecular Characteristics.

Background Specific molecular characteristics of invasive breast cancer have been linked to an increased risk of early relapse. Similarly, ductal carcinoma in situ (DCIS) displays a comparable molecular profile, although their prevalence and implications are not yet fully understood. Aims and objectives The study design defined a multivariable statistical approach aimed at describing the interplay between the histopathological features of ductal carcinoma in situ (DCIS) and their molecular profile. The objective was to explore the correlations between the histopathological features of DCIS (tumor location, DCIS grade, DCIS type, and presence or absence of comedo necrosis) and various biomarkers like estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2/neu), androgen receptor (AR), and epidermal growth factor receptor (EGFR), in addition to the Ki-67 labeling index. Methods In this retrospective study, we selected and analyzed 100 diagnosed cases of ductal carcinoma in situ (DCIS) to represent various subtypes, grades, and morphological characteristics. A detailed histopathological review and immunohistopathological staining for ER, PR, HER2/neu, AR, EGFR, and Ki-67 were performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks. Molecular subtyping was done based on the biomarker analysis into luminal A, luminal B, luminal HER2/neu, HER2/neu enriched, and triple-negative subtypes. Statistical analysis was done to examine the correlation between tumor location, histopathological features of ductal carcinoma in situ (DCIS), and the expression of the immunohistochemical markers and the molecular subtypes. Results The majority of cases exhibited positivity for estrogen receptor (ER) and progesterone receptor (PR). A strong association was observed between histopathological features (DCIS grade, type, and comedo necrosis) of DCIS and ER/PR status. Additionally, a significant correlation was found between ductal carcinoma in situ (DCIS) grade and HER2/neu status. However, no association was identified between histopathological features and AR or EGFR status. Contrary to expectations, triple-negative DCIS did not show the most aggressive behavior, whereas HER2/neu-positive tumors, particularly high-grade ones, exhibited more aggressive features. No low-grade cases of luminal HER2/neu and HER2/neu-enriched tumors were found. A higher Ki-67 labeling index was found in cases with grade 3 and solid and comedo architectural types of DCIS, while low-grade tumors had a lower Ki-67 labeling index. Conclusion These findings suggest that hormone pathways play a crucial role in ductal carcinoma in situ (DCIS) progression, but the molecular interactions are complex and extend beyond simple binary associations. The complex relationship between the histopathological features of ductal carcinoma in situ (DCIS) and its hormone receptor status warrants further investigation with a larger sample size to fully understand the underlying mechanisms. The results challenge the expectation that triple-negative DCIS is the most aggressive subtype, highlighting the need for further research into the prognostic significance of different DCIS subtypes.

Biomarkers for prognosis of meningioma patients: A systematic review and meta-analysis.

Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.

Abstract PO1-14-10: Comprehensive clinicogenomic characterization of inflammatory breast cancer

Abstract BACKGROUND: Inflammatory breast cancer (IBC) is a rare type of breast cancer associated with a unique clinical presentation and overall poor outcomes, recognized as a distinct category by the AJCC staging system. The biological mechanisms driving the IBC phenotype are relatively undefined—partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Here, we report one of the largest, subtype-informed clinicogenomic characterizations of IBC to date. METHODS: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing (OncoPanel, up to 447 cancer-associated genes) was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between IBC and non-IBC cases. Median follow-up was 28.1 months. RESULTS: Our profiled cohort included 140 patients with IBC specimens (n = 68 primary tumors, 72 metastatic tumors) and 2317 patients with non-IBC specimens (n = 702 primaries, 65 local recurrences, 1550 metastases). Of these, 87.4% of patients were White, 4.7% Black, 3.6% Asian or Pacific Islander, and 4.3% other/unknown. Clinicopathologic differences between IBC and non-IBC cases were consistent with previous reports—including younger age at diagnosis of metastatic disease (51 vs 54 years, p = 0.04), and a higher proportion of grade 3, estrogen receptor-negative and HER2-positive tumors (p < 0.001). Among the hormone-receptor (HR)-positive subtype, IBC tumors showed a significant enrichment in Luminal B (LumB)-inferred disease (62.5% vs 39.8%, p < 0.005), defined as tumors with grade 3 or progesterone receptor staining < 10%. The most recurrent somatic alterations spanning all subtypes in IBC were TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis accounting for HR and HER2 status revealed a significant enrichment in TP53 SNVs in IBC vs non-IBC (OR 2.08 [95% CI 1.34-3.24], adjusted p-value 0.04). Frequency of TP53 alterations in IBC vs non-IBC cases was 85.1% vs 64.3% in HER2-positive and 50.0% vs 27.7% in HR-positive disease—with an enrichment of TP53 mutations in IBC LumB-inferred tumors vs non-LumB (64% vs 26%, p < 0.05). When comparing HR+ IBC LumB vs HR+ non-IBC LumB cases, TP53 mutations were again enriched (p < 0.05)—suggesting LumB-like histopathology is not the only driving feature of TP53 enrichment in HR+ IBC. TMB did not differ substantially between IBC and non-IBC and no other statistically significant enrichments were observed, including when grouping mutations into six canonical cancer pathways (cell cycle, Notch signaling, PI3K pathway, RTK/RAS signaling, TP53 pathway and WNT signaling). CONCLUSIONS: Taken together, this study provides a comprehensive landscape of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC. Our data support a lack of major genomic differences other than enrichments in TP53 mutations and an associated LumB-like histopathology. These results both reinforce the importance of TP53 mutations in IBC biology and suggest additional analyses beyond somatic DNA-level changes are warranted. Future efforts with the DFCI IBC cohort will assess germline-somatic interactions, non-genomic or transcriptomic characterizations, and potential environmental influences to better understand the mechanisms driving this unique disease. Citation Format: Nolan Priedigkeit, Beth Harrison, Melissa Hughes, Robert Shue, Yvonne Li, Gregory Kirkner, Claire Remolano, Sarah Strauss, Janet Files, Anne-Marie Feeney, Ayesha Mohammed-Abreu, Ana Garrido-Castro, Romualdo Barroso-Sousa, Brittany Bychkovsky, Faina Nakhlis, Jennifer Bellon, Tari King, Bruce Johnson, Lynette Sholl, Deborah Dillon, Beth Overmoyer, Sara Tolaney, Andrew Cherniack, Nancy Lin, Filipa Lynce. Comprehensive clinicogenomic characterization of inflammatory breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-10.

Abstract 6546: Spatial immunology landscapes that correlate with survival in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by negative immunohistochemistry staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Treatment options for TNBCs are limited due to lack of tumor-specific targeted therapies, resulting in poor prognosis and patient survival. This is exacerbated by lack of prognostic markers of response. While current studies suggest tumor immune interactions are important, current immune activity quantifications, such as scores quantifying abundance of tumor-infiltrating lymphocytes (TILs), are not sufficient to define tumor immune status. We used imaging mass cytometry (IMC) to measure 33 markers on primary tumors of 100 patients undergone chemotherapy with long-term follow-up to explore the tumor immune microenvironment of TNBCs. Concordant with previous studies, a higher ratio of T-cells was associated with response to chemotherapy and longer overall survival (adjusted p-value<0.05). Moreover, using Kmeans clustering we identified 13 distinct cellular neighborhoods, reflective of the heterogenous nature of TNBCs. Among others, we identified a neighborhood, characterized by low CD14+ expression, low cytokeratin, high vimentin expression and high CD45RO, that contributes highest impact on correlation with overall survival (adjusted p-value<0.01). These results suggest an important role for memory T cells in the stroma. Thus, resolving spatial organization of the tissue is important to understanding patient response to therapy in TNBCs. Citation Format: Ali Foroughi pour, Jan Martinek, Te-Chia Wu, Santhosh Sivajothi, Zichao Liu, Jie Zhou, David Rimm, Paul Robson, Katherine Bates, Karolina Palucka, Jeffrey H. Chuang. Spatial immunology landscapes that correlate with survival in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6546.

Abstract 3575: The estrogenic endocrine disrupting compounds bisphenol-a (BPA) and alpha-zeranol (aZAL) induce early mammary hyperplasia in female ACI rats

Abstract Endocrine disrupting compounds (EDCs) found in food-grade plastics, drinking water, and foodstuffs, pose a threat to human health. Estrogenic EDCs are capable of binding and activating the estrogen receptor (ER). Since breast tissue relies on estrogen signaling for growth and renewal, excessive estrogen stimulation is associated with breast cancer development. Breast cancer is a leading cause of cancer-related death in women. Only 5-10% of all breast cancer cases can be attributed to genetic causes, and the proportion of breast cancers of the luminal subtype are increasing in the United States for reasons unknown. Estrogenic EDCs may be able to initiate breast cancers through their estrogenic activities. The present study assessed two EDCs: the plasticizer bisphenol-A (BPA) and the mycotoxin alpha-zeranol (aZAL). To assess the estrogenic effects of these EDCs in an in vivo model, we utilized the ACI rat strain due to its sensitivity to estrogen-induced mammary carcinogenesis. The hypothesis of this work was that BPA and aZAL will induce mammary gland proliferation and estrogen signaling at early timepoints post-exposure. Estrogen, BPA, or aZAL were implanted into the backs of female ACI rats in silastic tubes at either a 9 gram doses. At a timepoint of 5 days post implantation, we saw no overt toxicity of our treatment. Both BPA and aZAL resulted in increased glandular proliferation and hyperplasia in a comparable manner to estrogen. Immunohistochemistry and qPCR revealed that the estrogen signaling marker progesterone receptor (PGR) was significantly upregulated in the estrogen, BPA, and aZAL treatment groups compared to control. The percent positivity of PGR staining in the mammary glands were 21.5% +/- 4.2%, 25.7% +/- 1.7%, 27.9% +/- 3.8%, and 8.18% +/- 2.5% respectively. Additionally, PCNA, a marker of cell proliferation, was significantly upregulated in the estrogen and aZAL treatment groups. The percent positivity of PCNA staining in the mammary glands were 7.67% +/- 2.56%, 49.6% +/- 5.2%, and 41.0% +/- 11.5% respectively. Additionally, the weight of the pituitary gland, an estrogen-sensitive endocrine organ, significantly increased in both the estrogen and aZAL treatment groups. Overall, this study demonstrated that the estrogenic EDCs BPA and aZAL induced mammary gland proliferation and hyperplasia in a comparable manner to estrogen. This is concerning due to the routine detection of these two compounds in human biosamples. More information is needed to assess the risk of exposure to these compounds as it pertains to breast cancer and other hormonal cancers. Citation Format: Cassandra Winz, Ba Liu, Caroline Xie, Shlok Rohatagi, Eric Li, Philip Furmanski, Nanjoo Suh. The estrogenic endocrine disrupting compounds bisphenol-a (BPA) and alpha-zeranol (aZAL) induce early mammary hyperplasia in female ACI rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3575.

Expanding the Spectrum of NR4A3 Fusion–Positive Gynecologic Leiomyosarcomas

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3 fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3 rearrangements with PGR and novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3 fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema–like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3 RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3 rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3 fusion–positive gynecologic leiomyosarcomas.

Abstract B015: A novel Cluster 3 Endometrial Cancer PDX model to test hormone therapy regimens

Abstract Endometrial cancer is the most commonly diagnosed gynecologic cancer and continues to rise in incidence and mortality rates worldwide. With the evaluation of large datasets including the TCGA, endometrial cancers have been subdivided into four different cluster groups based on molecular characteristics. The most common subtype of endometrial cancer is the Cluster 3 category, demarcated by the expression of estrogen receptors (ER) and progesterone receptors (PR) with the potential to respond to hormonal therapy. However, Cluster 3 tumors frequently lose hormone receptor expression over time, particularly PR, making them resistant to treatment. Although numerous cell line models exist to study this disease, there is a need for improved models to select best treatment options for the specific types of endometrial cancers. Here, we describe the development of an endometrial cancer patient derived xenograft (PDX), EC-PDX3. The initial tumor from which EC-PDX3 was derived was a low-grade endometrioid endometrial carcinoma that contained a low number of somatic copy number alterations. The tumor initially tested robustly positive for both ER and PR in the donor patient as well as in initial passages in athymic mice, making this model valuable for hormone therapy research. In these studies, EC-PDX3 cells were grown within immunodeficient NSG mice. We performed H&E, ER and PR staining prior to experimentation and found that while ER remained highly positive, PR levels were significantly downregulated, indicating the development of a hormone resistant state similar to that occurring in patients over time. To determine if these cells respond to hormonal therapy and if PR expression could be induced, mice were initially treated with estradiol to enhance PR expression. Next, mice were further treated with progesterone or onapristone, an experimental progestin agonist/antagonist with previously reported encouraging activity in advanced endometrial cancer in phase I and II trials. Tumors were measured weekly to determine hormone effects on cancer growth. Mice treated with estradiol alone showed substantially larger tumor growth as compared to the estradiol + progesterone and estradiol + onapristone treatment groups, indicating that hormone sensitivity was likely re-instated. RNA sequencing using Ishikawa cells in culture revealed the transcriptional effects of estradiol, progesterone and onapristone which complement the data obtained from EC-PDX3 bearing mice treated similarly. These studies identify interesting growth inhibitory effects of onapristone in endometrial cancer cells primed with estradiol including the significant induction of the cell cycle regulators such as p21 and genes involved in apoptosis. In addition, EC-PDX3 provides a model to assess hormonal therapy in Cluster 3 tumors that initially respond but develop resistance to treatment over time. Citation Format: Kimberly K. Leslie, Lane E. Smith, Jamie Padilla, Adrian Quintana. A novel Cluster 3 Endometrial Cancer PDX model to test hormone therapy regimens [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B015.

Vulvar Hidradenoma Papilliferum.

This study examines the clinical and pathological characteristics, immune profile, histological occurrence, diagnosis, and differential diagnosis of vulvar hidradenoma papilliferum. An analysis was conducted on clinical data, histological patterns, and immunohistochemical findings from 45 cases of vulvar hidradenoma papilliferum, and relevant published articles were reviewed. Simultaneously, high-risk HPV typing was performed on these 45 cases. The 45 cases of vulvar hidradenoma papilliferum displayed tumor sizes ranging from 0.3 to 2.0 cm and were observed to be pink or red in appearance. Vacuolated cytoplasm, large abnormal nuclei, distinct nucleoli, and scattered eosinophilic luminal secretions were observed in the glands. Positive staining for CK7 and progesterone receptor (PR) with focal mammaglobin and GCDFP-15 expression was found through immunohistochemistry. CK20 staining was noted as negative. Hidradenoma papilliferum is a rare benign tumor that originates in secretory glands. The diagnosis of this condition is aided by gross and immunohistochemical results, and differentiation from other conditions is necessary.

A prognostic model for tumor recurrence and progression after meningioma surgery: preselection for further molecular work-up.

The selection of patients for further therapy after meningioma surgery remains a challenge. Progress has been made in this setting in selecting patients that are more likely to have an aggressive disease course by using molecular tests such as gene panel sequencing and DNA methylation profiling. The aim of this study was to create a preselection tool warranting further molecular work-up. All patients undergoing surgery for resection or biopsy of a cranial meningioma from January 2013 until December 2018 at the University Hospital Zurich with available tumor histology were included. Various prospectively collected clinical, radiological, histological and immunohistochemical variables were analyzed and used to train a logistic regression model to predict tumor recurrence or progression. Regression coefficients were used to generate a scoring system grading every patient into low, intermediate, and high-risk group for tumor progression or recurrence. Out of a total of 13 variables preselected for this study, previous meningioma surgery, Simpson grade, progesterone receptor staining as well as presence of necrosis and patternless growth on histopathological analysis of 378 patients were included into the final model. Discrimination showed an AUC of 0.81 (95% CI 0.73 - 0.88), the model was well-calibrated. Recurrence-free survival was significantly decreased in patients in intermediate and high-risk score groups (p-value < 0.001). The proposed prediction model showed good discrimination and calibration. This prediction model is based on easily obtainable information and can be used as an adjunct for patient selection for further molecular work-up in a tertiary hospital setting.

Discordance of Oncotype DX scores in synchronous bilateral and unilateral multifocal breast cancers.

Oncotype DX, a 21-gene expression profiling test, has become standard of care in the management of estrogen receptor (ER)-positive breast cancer. In multifocal tumors, it is unclear whether testing of the different foci is necessary. We evaluated the concordance of Oncotype DX recurrence scores (RS) between 2 tumor foci in synchronous bilateral or unilateral multifocal tumors and characterized pathological predictors of discordance. We reviewed 713 ER+, HER2- primary invasive breast cancer patients with Oncotype RS and identified 17 bilateral synchronous patients (34 tumors) and 13 unilateral multifocal patients (26 tumors) with available Oncotype RS on all foci. Discordance in Oncotype RS between synchronous tumors was recorded and associations with clinicopathologic features including tumor size, histology, Nottingham histologic grade, progesterone receptor staining, and Ki67 index were analyzed. Bilateral synchronous tumors were present in older patients (median age 59years) and had larger tumor (median size 17mm) and more discordant histology (10/17, 59%) as compared to unilateral multifocal tumors (median age 49years, p < 0.01; median tumor size 12mm, p = 0.01; discordant histology 2/13, 15%, p = 0.03). Oncotype RS were discordant in 47% (8/17) of bilateral and 54% (7/13) of unilateral multifocal tumors. Concordant Oncotype RS was associated with similar histologic grade and Ki67 index in 78% (7/9) of bilateral and 100% (6/6) of multifocal tumors. In contrast, only 25% (2/8) of bilateral (p = 0.06) and 14% (1/7) of unilateral multifocal (p < 0.01) cases with discordant Oncotype RS had concordant histology grades and Ki67 levels. In synchronous tumors with discordant Oncotype RS and Ki67 index, all (4/4) foci with higher RS had higher Ki67 index. Discordance of Oncotype RS is common in both bilateral and unilateral multifocal breast cancer and is likely associated with discordant histologic grade or Ki67.

Placental histology for targeted risk assessment of recurrent spontaneous preterm birth

Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth. Only a few identifiable clinical risk factors can be referenced in counseling for recurrent preterm birth. Furthermore, treatment using progesterone supplementation has not consistently prevented preterm birth among high-risk patients, but it may be effective in a subset of those patients. Placental pathology from a previous pregnancy may be used to predict which patients will experience a recurrent preterm birth or to identify a subset of patients more likely to respond to treatment with antenatal progesterone. This study aimed to determine if histologic patterns are associated with recurrent preterm birth among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua are associated with the response to progesterone supplementation with intramuscular 17-hydroxyprogesterone caproate. This was a retrospective cohort study at a single institution of women with singleton pregnancies with an index spontaneous preterm birth and a subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available for the index spontaneous preterm birth. A logistic regression was used to determine if there were independent associations between 4 histologic types (acute inflammation, maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammation) and recurrent preterm birth. For the secondary endpoint, 17-hydroxyprogesterone caproate response was defined as prolonging gestation by >3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered <3 weeks beyond the gestational age in the index pregnancy but at ≥39 weeks' gestation were excluded. A logistic regression was used to assess the independent association between placental histology and 17-hydroxyprogesterone caproate response. Sensitivity analyses were completed using only patients with an index birth <36 weeks' gestation, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term birth and 20 patients with a subsequent spontaneous preterm birth. The percentage of cells in the maternal decidua positive for progesterone receptors was correlated with the subsequent pregnancy outcome. A total of 352 patients were included. Acute inflammation was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by chronic inflammation (40.9%) and maternal vascular malperfusion (31.3%). No histologic type was independently associated with recurrent preterm birth. A total of 155 patients received 17-hydroxyprogesterone caproate in a second pregnancy. Low-grade acute inflammation was significantly associated with a decreased likelihood of 17-hydroxyprogesterone caproate response. Low-grade maternal vascular malperfusion among those with an index pregnancy delivered at <36 weeks' gestation was significantly associated with a more than 4 times increased likelihood of 17-hydroxyprogesterone caproate response when excluding those with a subsequent iatrogenic preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth. Although acute inflammation was prevalent among spontaneous preterm births, more than half of the spontaneous preterm births were not associated with acute inflammation. Low-grade acuteinflammation was associated with a significantly decreased response to 17-hydroxyprogesterone caproate supplementation. Low-grade maternal vascular malperfusion was associated with a 4-fold increased likelihood of 17-hydroxyprogesterone caproate response among those with index deliveries <36 weeks' gestation. Further work is needed to determine if placental pathologic examination can be used to target treatment in subsequent pregnancies to prevent recurrent preterm birth.

Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer.

The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC). 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant. HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC. Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.

The role of local expression of hormone receptors in the genesis of idiopathic tracheal stenosis.

Tracheal stenosis in adults is usually the result of mechanical injuries either from direct trauma, tracheotomy or intubation. Idiopathic stenosis in the cricotracheal section is a rare condition and occurs almost exclusively in females. Therefore, an influence of the female sexual hormones estrogen and progesterone has been assumed previously. Tracheal specimens of 27 patients who received tracheal resection for either idiopathic tracheal stenosis (ITS) (n=11) or posttraumatic tracheal stenosis (PTTS) (n=16) between 2008 and 2019 in our surgical department were included and retrospectively analyzed. Immunohistochemical staining of tracheal specimens concerning the hormone receptor status of progesterone and estrogen was performed. While post-tracheotomy stenosis occurred in males (n=6) as well as in females (n=10), none of the patients with idiopathic stenosis were males. All of the idiopathic stenosis (n=11; 100%) showed a strong expression of the estrogen receptors (ERs) in the fibroblasts and expression of progesterone receptors (PRs) in fibroblasts in 8 of 11 (72.7%). In the post-tracheotomy patients, only 3/16 (18.8%) showed slight staining of PRs and 6/16 (37.5%) of ERs. Of those, only one male patient presented with expression of ERs and PRs and another male patient presented with isolated PRs. Oral intake of hormone compounds was seen in 11/27 (40.7%) patients: 7/11 (63.6%) in the ITS group and 4/16 (25%) in the PTTS (noteworthy that the PTTS group included 6 male patients). Although the number of patients is small, our results show that the expression of female sexual hormone receptors in the fibroblasts of the trachea is a persistent finding in ITS. Surgery provided good results with a favorable long-term outcome without recurrence of stenosis for ITS and PTTS. Further investigation with a special focus on hormones is needed to assist in the prevention of this rare disease.

Malignancy risk factors and prognostic variables of pancreatic mucinous cystic neoplasms in Chinese patients.

Pancreatic mucinous cystic neoplasms (MCNs) represent one of the precursor lesions of pancreatic ductal adenocarcinoma, and their detection has been facilitated by advances in preoperative imaging. Due primarily to the rarity of MCNs, however, there is limited knowledge regarding the prognostic variables and high-risk factors for malignant transformation. A more comprehensive and nuanced approach is necessary to fill this gap and provide a basis for improved treatment decisions and patient outcomes. To investigate the high-risk factors associated with malignant MCNs and to explore the prognostic factors of MCN with associated invasive carcinoma (MCN-AIC). All cases of resected MCNs from a single high-volume institution between January 2012 and January 2022 were retrospectively reviewed. Only cases with ovarian-type stroma verified by progesterone receptor staining were included. Preoperative features, histological findings and postoperative course were documented. Multivariate logistic regression was employed to investigate variables related to malignancy. Survival analysis was performed using the Kaplan-Meier curve, and the prognostic factors were assessed to evaluate the postoperative course of patients with MCN-AIC. Among the 48 patients, 36 had benign MCNs, and 12 had malignant MCNs (1 high-grade atypical hyperplasia and 11 MCN-AIC). Age, tumour size, presence of solid components or mural nodules and pancreatic duct dilatation were identified as independent risk factors associated with malignancy. The follow-up period ranged from 12 mo to 120 mo, with a median overall survival of 58.2 mo. Only three patients with MCN-AIC died, and the 5-year survival rate was 70.1%. All 11 cases of MCN-AIC were stage I, and extracapsular invasion was identified as a prognostic factor for poorer outcomes. The risk factors independently associated with malignant transformation of MCNs included age, tumour size, presence of solid components or mural nodules, and pancreatic duct dilatation. Our study also revealed that encapsulated invasion was a favourable prognostic factor in MCN-AIC patients.

Ultrastructural and Immunohistochemical Characterization of Maternal Myofibroblasts in the Bovine Placenta around Parturition

Myofibroblasts are contractile cells that exhibit features of both fibroblasts and smooth muscle cells. In the synepitheliochorial placenta of the cow myofibroblasts are found in the maternal stroma. However, a deeper understanding of the structure and function of the stromal myofibroblasts in the developed bovine placenta is still missing. Thus, immunohistochemical and ultrastructural analyses in bovine term placentomes, compared to non-pregnant caruncle samples, were conducted. To investigate functional aspects, contractility of placentomal caruncle slices was assessed in an in vitro contraction assay. Additionally, a three-dimensional reconstruction of a bovine placental myofibroblast was created. Immunofluorescent staining revealed a characteristic pattern, including cytoplasmic expression of α-smooth muscle actin, strong perinuclear signal for the intermediate filament vimentin and nuclear progesterone receptor staining. Ultrastructurally, stress fibers, extended cisternae of the rough endoplasmic reticulum and perinuclear intermediate filaments were observed. Moreover, in vitro stimulation with angiotensin-II, but not with prostaglandin F2α, induced contraction of placental caruncle tissue. Altogether, these results indicate that progesterone-responsive myofibroblasts represent a mesenchymal phenotype that is involved in the contractile properties of bovine placental stroma. Therefore, the present findings suggest a potential involvement of myofibroblasts in post-partum events of cattle, i.e., expulsion of fetal membranes and uterine involution.

Anaplastic mammary carcinoma in a captive jaguar (Panthera onca)

ABSTRACT A captive female of jaguar (Panthera onca), 12 years old, presenting an 8-day history of anorexia and lethargy, died in its enclosure in Manaus (Amazonas, Brazil). The necropsy revealed an abdominal multinodular ventral plaque into the mammary region. Additionally, in several locations of the subcutaneous tissue, there were multiple metastatic nodules of firm texture. Metastases were also observed in the lymph nodes, heart and lungs. The immunohistochemistry results revealed the cytoplasmic staining for cytokeratin on neoplastic cells, mild staining (+) for E-cadherin, moderate staining (++) for estrogen and progesterone receptors, and about 50 to 70% of staining for Ki-67. The neoplastic cells were negative for vimentin staining. Therefore, the histopathological examination led to a diagnosis of metastatic anaplastic mammary carcinoma, which is an unusual condition in wild felines.

Distinct clinicopathological features of ovarian endometriosis after long-term exposure to mifepristone.

Mifepristone has been used to treat endometriosis, but it can cause a constellation of endometrial alterations. Our study investigated the effects of long-term mifepristone on ovarian endometriosis. We retrospectively analyzed the clinicopathological changes of ovarian endometriosis in 11 Chinese patients after long-term low-dose mifepristone therapy and compared these alterations with those observed in eutopic endometrium and adenomyosis side-by-side. Immunohistochemistry was applied to investigate estrogen receptor (ER), progesterone receptor (PR), and Ki67 expression in eutopic and ectopic endometrium. Nearly all patients had a pelvic mass and elevated serum CA125 levels. The ovarian lesions were grossly solid, cystic-solid, or cystic. They had a grayish-reddish appearance and a fleshy, honeycomb-like cut surface. The ovarian lesions shared morphological features with the uterine endometrium, and they were characterized by dilated, crowding endometrial glands with non-physiological changes. Immunostaining revealed consistent staining for ER and PR and a low Ki67 index in both eutopic and ectopic endometrium. Our findings suggest that ovarian endometriosis can mimic an endometrioid borderline tumor after long-term mifepristone administration. Careful histological assessment and related clinical information are critical for the correct interpretation of these rare entities.

Histopathological Evaluation of Estrogen Receptors, Progesterone Receptors, and Human Epidermal Growth Factor Receptor-2/Neu Expressions in Breast Carcinoma and their Correlations with Other Prognostic Factors

Background: Breast carcinoma is a leading cause of death among women. Factors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER-2/neu) have important prognostic and predictive value. Aim: The aim of the study is to demonstrate ER, PR, and HER-2/neu expression in breast cancer specimens and to correlate these expressions with other prognostic factors such as tumor size, type, grade, and lymph node status. Methods: This prospective study included 70 cases of female breast carcinoma. Histopathological evaluation of all cases done and tumor size, site, presence, or absence of lymph node was recorded. Typing of tumor, grade, and lymph node status were determined. Immunohistochemical staining for ER, PR, and HER-2/neu of breast lesions was done, and the data were analyzed to find out any correlation of expression of ER, PR, HER-2/neu with the above prognostic factors. Results: The majority of patients were in 41–50 years (44.29%). Most of tumors were 2–5 cm in size and the infiltrating duct carcinoma-not otherwise specified was the commonest type. ER and PR expression decreases (P = 0.02340 and P = 0.02413 respectively), while HER-2/neu expression increases with increase tumor size (P = 0.02289). ER and PR expression were low while Her-2/neu expression was more in higher tumor grade (P = 0.022472, P = 0.04149 and P = 0.03339 respectively). No significant association was identified between ER, PR, HER-2/neu and number of metastatic lymph node. Conclusion: ER, PR, and HER-2/neu status correlates well with histopathological grading and tumor size. However, no significant association is seen with cancer type and lymph node status.

Uterine tumours with myogenic differentiation harbouring SRF::RELA fusions.

In 2017, a subset of cellular variants of myofibroma and myopericytoma with a smooth muscle-like immunophenotype and harbouring recurrent SRF::RELA gene fusions was reported. Although the anatomical distribution was found to be quite broad, no tumours with these gene fusions in the female reproductive system have been illustrated to date. Herein, we report the histological and immunophenotypical features of three uterine tumours with SRF::RELA gene fusions. Microscopically, all three tumours were composed of cellular oval to spindle cells arranged in intersecting fascicles with variable amounts of collagen and a rich capillary network. Mitotic figures were scant. Regarding immunohistochemistry, diffuse staining for desmin, oestrogen receptor and progesterone receptor was observed in all three cases. The first case exhibited focal staining for h-caldesmon, whereas the latter two cases had diffuse staining. Furthermore, SRF::RELA rearrangement was observed in all three cases by using next-generation sequencing (NGS). Follow-up, ranging from 11 to 15 months, was available for these three patients, all of whom were well without evidence of disease. In conclusion, we reported a special group of uterine neoplasms with myogenic differentiation harbouring SRF::RELA rearrangement. Although the follow-up time was limited, morphological characteristics and other studies with follow-up data supported that this type of uterine neoplasm appeared to behave in a benign manner. Further studies with longer follow-up are needed to clarify the biological nature of this particular type of uterine tumour.

Meningothelial Hamartoma of the Scalp: Clinicopathologic Review of an Unusual Tumor Mimicking a Vascular Neoplasm With Review of Literature

An unusual benign skin lesion is reported in a 19-year-old man with no significant medical history. The lesion had been present since he was an infant and had been slowly enlarging over the past 15 years. The lesion caused pain and discomfort, and the patient underwent an excisional biopsy. Histologic examination showed a subcutaneous lesion with ill-defined borders and peripheral areas of infiltration between adnexal structures. The lesion was composed of small round to ovoid cells embedded in a collagenous stroma with prominent cystic pseudovascular appearing channels causing a pseudopapillary or lymphangitic appearance that mimicked a vascular neoplasm. Immunohistochemistry performed showed positive staining for EMA, progesterone receptor, D2-40, and vimentin within the lesional cells. The tumor cells were negative for cytokeratin AE1/AE3, CD34, CD31, HHV-8, STAT6, SMA, Desmin, S-100, Melan A, and HMB45. A next-generation sequencing study using a hybrid capture-based panel examining 50 commonly mutated genes in human neoplasia was performed and showed no molecular alterations suggesting a nonneoplastic nature. Based on the clinical presentation, histologic features, and results of ancillary studies, the case was diagnosed as a hamartoma of the scalp with meningothelial-like elements. Reported cases of this lesion have behaved in a benign manner; however, as the histologic differential includes low-grade malignant vascular neoplasms such as angiosarcoma, it is important to recognize the salient features of this lesion.