Serous Component Research Articles

Rarely Observed Histopathological Subtypes of Endometrial Malignant Tumors in a Tertiary Care Center: A Case Series.

Introduction Endometrial cancer, one of the most prevalent gynecological malignancies, represents a significant contributor to global mortality and morbidity. The histological subtype of this cancer is pivotal in treatment planning and patient risk stratification. This case series, comprising seven cases, underscores the significance of rare endometrial cancer variants and the importance of ancillary studies, specifically immunohistochemistry, in comprehending and diagnosing the condition. Materials and methods The data of all the rare histological subtypes of malignant endometrial tumors encountered from April 2021 to April 2024 were collected. The data collected included age; risk factor; histological type; tumor, node, metastasis (TNM) stage; the International Federation of Gynecology and Obstetrics (FIGO)grade; P53; and mismatch repair (MMR) status. The histopathology specimens were reviewed using a Labomed microscope (LX500) manufactured in India. Images were taken and added wherever necessary, and the results were studied, analyzed, clinically correlated, and are shown in tables. Results Seven rare histopathological subtypes of malignant endometrial tumors were encountered in this period in this tertiary care center. This included mesonephric like adenocarcinoma, high-grade carcinosarcoma, carcinosarcoma with the serous and chondrosarcomatous components, clear cell carcinoma of endometrium, endometrial stromal sarcoma with smooth muscle differentiation, endometrial stromal sarcoma, and undifferentiated sarcoma with focal myxoid degeneration. Conclusion Diagnosis of uncommon endometrial carcinomas proves to be challenging due to their various histological subtypes, most often with overlapping features. The cornerstone of effective care lies in collaboration with clinicians, radiologists, and pathologists to identify these lesions as early as possible using a multidisciplinary approach for optimal patient outcome management.

High-grade Endometrial Carcinoma With Serous and Colorectal Carcinoma-like Components: Unique Morphology in Correlation With Immunohistochemical and Molecular Findings.

Endometrial carcinoma with intestinal differentiation/colorectal carcinoma-like (CRC-like) features is rare with few cases reported to date. Those described are mainly endometrioid carcinomas with intestinal differentiation. We report a case of high-grade endometrial carcinoma with serous and intestinal/CRC-like components. The gross, histologic, immunohistochemical, and molecular features are described for both components of the tumor in the initial diagnostic biopsy and subsequent resection specimen. The diagnosis of primary endometrial carcinoma with serous and CRC-like components is supported by immunohistochemical and molecular findings, as well as clinical workup. The rarity of this phenomenon poses diagnostic challenges. In addition, the literature is reviewed with specific emphasis on the molecular and pathologic features of mixed endometrial carcinomas, including those with intestinal/CRC-like features.

Seromucinous tumors of ovary: A case series

Seromucinous neoplasms are new category of ovarian epithelial tumor in the 2014 revised World Health Organization classification. Surface epithelial neoplasms are the most common ovarian tumors. Based on the degree of stratification and the presence or absence of invasion, these epithelial proliferations are further divided into benign, borderline, and malignant categories. Benign tumors are divided into three subtypes: cystadenoma (cystic areas), cystadenofibroma (cystic and fibrous areas), and adenofibroma (predominantly fibrous sections). Serous adenofibromas are rare variant of serous surface epithelial tumors. They affect females between the ages of 15 and 65 and make up 1.7% of all benign ovarian tumors. Serous tumor with a solid, fibrous component is designated as serous cystadenofibroma in which both serous and mucinous components are closely intermixed. Seromucinous adenofibroma is a benign cystic neoplasm composed of glands and cysts lined by an admixture of bland mullerian type epithelium which includes ciliated, endocervical type mucinous, and endometroid. They have a characteristic prominent fibromatous hypocellular stroma which helps differentiate it from the commoner cystadenoma. Seromucinous borderline tumors is 10% -20% of all epithelial ovarian tumors. Develops in younger age, usually bilateral in upto 40%, associated with endometriosis. We discuss about four different cases of seromucinous tumor reported in our institute.

PON3::LCN1 and HTN3::MSANTD3 Gene Fusions With NR4A3/NR4A2 Expression in Salivary Acinic Cell Carcinoma.

Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.

A pilot image-based analysis of changes in pigment epithelial detachment composition in neovascular age-related macular degeneration

We report changes in pigment epithelial detachment composition indices (PEDCI), derived using an automated algorithm, in six eyes with neovascular age-related macular degeneration (nAMD) through 84 months. Changes in serous, neovascular, and fibrous components (PEDCI-S, N, and F, respectively) were compared. PEDCI-S reduced from 0.60 ± 0.21 (baseline) to 0.17 ± 0.20 (84 months; P = 0.03). PEDCI-N showed a significant increase from 0.30 ± 0.15 to 0.71 ± 0.21 (P = 0.01), whereas PEDCI-F changed minimally (0.10 ± 0.09 to 0.13 ± 0.11; P = 0.69) at 84 months. Overall, PEDCI-S showed a gradual reduction, whereas PEDCI-N increased relative to other constituents through 84 months. PEDCI-F, a surrogate marker of scarring, was not predictive of final visual acuity.

Pigment epithelial detachment composition indices in central serous chorioretinopathy as a biomarker for disease activity: A computational methodology and 1 year outcomes.

Investigation of pigment epithelial detachment (PED) characteristics in central serous chorioretinopathy (CSCR) is underrepresented in the literature. We present a novel computational approach to quantify PED composition indices (PEDCI) in CSCR and track changes over time. 34 eyes with active CSCR were analyzed quarterly over a 1-year period. Cases were categorized into acute and chronic CSCR depending on a symptom duration of less than 3 months or more than 3 months respectively. PED, retinal and choroidal dimensions were manually measured, and interval changes were compared using repeated measures of variance ANOVA. PED composition analysis involved manual segmentation followed by automated sub segmentation of PED areas to identify serous, neovascular and fibrous tissues. PEDCI for each component was compared among cases of acute and chronic CSCR. CMT and NSD-h decreased by 65.2 µm (p = 0.01), and 86.5 µm (p < 0.01) respectively at 12 months. At baseline, 7/17 acute CSCR eyes and 8/15 chronic CSCR eyes had a concomitant PED; acute cases had both serous and neovascular components (PEDCI-S: 16.95%, PEDCI-N: 40.3%), whereas chronic cases only had a neovascular component (PEDCI-S: 0%, PEDCI-N: 30.5%). At 12-month follow-up, 6/7 of acute CSCR group and 6/8 chronic CSCR group had a concomitant PED; PEDCI-S was largest for acute CSCR (53.4%) and PEDCI-N was largest for chronic CSCR (46.7%). We identify a novel biomarker PEDCI to differentiate acute and chronic CSCR with higher PEDCI-S in acute CSCR, and higher PEDCI-N in chronic CSCR.

The comparison of pure uterine serous carcinoma and mixed tumor with serous component: a single-institution review of 91 cases

BackgroundPure uterine serous carcinoma (p-USC) and mixed tumors with serous component (m-USC) are aggressive subtypes of endometrial cancer associated with high mortality rates. This retrospective study aimed to compare clinicopathologic features and outcomes of p-USC and m-USC in a single center.MethodsThis study retrospectively reviewed patients diagnosed with USC at Peking University People’s Hospital between 2008 and 2022. T-tests and chi-square tests were used to compare clinicopathological characteristics between p-USC and m-USC. Kaplan-Meier survival curve and Cox regression analysis were used to analyze the impact of clinical and pathological variables on OS and PFS.ResultsAmong the 91 patients who underwent surgery, 65.9% (n = 60) were p-USC, and 34.1% (n = 31) were m-USC. Patients with p-USC had earlier menopause (P = 0.0217), a lower rate of progesterone receptor(PR) expression (P < 0.001), and were more likely to have positive peritoneal cytology (P = 0.0464). After a median follow-up time of 40 months, 28 (46.7%) p-USC and 9 (29%) m-USC patients had progression disease, 18 (30%) and 8 (25.8%) patients died of their disease. 5-year PFSR were 51.2% and 75.3%, respectively, and 5-year OS rates were 66% and 67.4%. Kaplan-Meier survival analysis showed that p-USC was more likely to relapse than m-USC (P = 0.034), but there was no significant difference in OS. Cox regression analysis showed that lymph node metastasis and surgical approach were risk factors for OS, and myoinvasion depth ≥ 1/2 was an independent risk factor for PFS.Conclusionsp-USC was more likely to relapse than m-USC, but there was no significant difference in OS between the two subtypes.

Comparative analysis of EZH2, p16 and p53 expression in uterine carcinosarcomas.

Introduction: The role of p16 and p53 immunohistochemistry in the diagnosis of rare and aggressive uterine carcinosarcoma (UCS) has been well established. However, enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a member of the polycomb group family is a relatively new biomarker, with limited published data on its significance in this tumor type. The goal of this study was to examine EZH2 expression in UCS and its components, in correlation with morphological features, and p16 and p53 staining patterns. Methods: Twenty-eight UCSs were included in the study. EZH2, p16 and p53 immunoreactivity were assessed independently by two pathologists in both tumor components (epithelial and mesenchymal). EZH2 and p16 immunostains were scored semiquantitatively: based on the percentage and intensity of tumor cell staining a binary staining index ("high- or low-expressing") was calculated. The p53 staining pattern was evaluated as wild-type or aberrant (diffuse nuclear, null, or cytoplasmic expression). Statistical tests were used to evaluate the correlation between staining patterns for all three markers and the different tumor components and histotypes. Results: High EZH2 and p16 expression and aberrant p53 patterns were present in 89.3% 78.6% and 85.7% of the epithelial component and in 78.6%, 62.5% and 82.1% of the mesenchymal component, respectively. Differences among these expression rates were not found to be significant (p > 0.05). Regarding the epithelial component, aberrant p53 pattern was found to be significantly (p = 0.0474) more frequent in the serous (100%) than in endometrioid (66.6%) histotypes. Within the mesenchymal component, p53 null expression pattern occurred significantly (p = 0.0257) more frequently in heterologous sarcoma components (71.4%) compared to the homologous histotype (18.8%). Conclusion: In conclusion, EZH2, p16 and p53 seem to play a universal role in the pathogenesis of UCS; however, a distinctive pattern of p53 expression appears to exist between the serous and endometrioid carcinoma components and also between the homologous and heterologous sarcoma components.

Mixed Endometrial Epithelial Carcinoma: Epidemiology, Treatment and Survival Rates-A 10-Year Retrospective Cohort Study from a Single Institution.

Mixed endometrial carcinoma (MEEC) refers to rare endometrial tumours that are composed of two or more distinct histotypes, at least one of which is serous or clear cell. The aim of this study was to evaluate the epidemiology, treatment outcomes and survival rates of patients with mixed endometrial carcinoma. The medical records of 34 patients diagnosed with MEEC between March 2010 and January 2020 were reviewed retrospectively. Clinicopathological variables and treatment strategies were assessed, and overall survival and disease-free survival rates were evaluated. The histology of endometrioid and serous component was found in 26 (76.5%) patients, followed by serous and clear-cell components (5/34, 14.5%) and mixed endometrioid serous and clear-cell components (3/34, 8.8%). The median age at diagnosis was 70 years (range 52-84), and the median follow-up time was 55 months. The 5-year disease-free survival and the 5-year overall survival were 50.4% and 52.4%, respectively. Advanced disease stage was identified as an independent predictor of inferior disease-free (<0.003) and overall survival (p < 0.001). Except for stage, none of the traditional prognostic factors was associated with disease recurrence or death from disease. MEECs represent rare high-risk endometrial carcinomas with significant diagnostic and treatment challenges. Undoubtedly, the implementation of a molecular analysis can offer further diagnostic and management insights.

Mixed clear cell/endometrioid and clear cell/serous carcinoma of the uterus are clinicopathologically similar to pure clear cell carcinoma: An NRG Oncology/Gynecologic Oncology Group (GOG-210) study of 311 women

ObjectivesClear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. MethodsThe term “mixed” was applied to tumors with multiple identifiable components, and “indeterminate” was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. ResultsOne hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. ConclusionIn clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.

Current Treatments for Diabetic Macular Edema.

Diabetic retinopathy is a major retinal disorder and a leading cause of blindness. Diabetic macular edema (DME) is an ocular complication in patients with diabetes, and it can impair vision significantly. DME is a disorder of the neurovascular system, and it causes obstructions of the retinal capillaries, damage of the blood vessels, and hyperpermeability due to the expression and action of vascular endothelial growth factor (VEGF). These changes result in hemorrhages and leakages of the serous components of blood that result in failures of the neurovascular units (NVUs). Persistent edema of the retina around the macula causes damage to the neural cells that constitute the NVUs resulting in diabetic neuropathy of the retina and a reduction in vision quality. The macular edema and NVU disorders can be monitored by optical coherence tomography (OCT). Neuronal cell death and axonal degeneration are irreversible, and their development can result in permanent visual loss. Treating the edema before these changes are detected in the OCT images is necessary for neuroprotection and maintenance of good vision. This review describes the effective treatments for the macular edema that are therefore neuroprotective.

Is the sarcomatous component (homologous vs heterologous) the prognostic “driving force” in early-stage uterine carcinosarcomas? A retrospective multicenter study

PurposeUterine carcinosarcomas (UCSs) are aggressive biphasic malignancies, with a carcinomatous/epithelial component and a sarcomatous/mesenchymal counterpart. The aim of this study was to evaluate the impact of the sarcomatous component (homologous vs heterologous) on the overall survival (OS) and progression-free survival (PFS).MethodsThis is a multicenter observational retrospective study conducted in patients with stage I and II UCSs.ResultsNinety-five women with histological diagnosis of early-stage UCSs were retrieved: 60 (63.2%) had tumors with homologous sarcomatous components, and 35 (36.8%) with heterologous. At univariate analysis, a stromal invasion ≥ 50%, the presence of clear cell, serous or undifferentiated carcinomatous component, the heterologous sarcomatous component and FIGO stage IB and II were shown to be variables with a statistically significant negative impact on PFS. Similarly, a depth of invasion ≥ 50%, the heterologous sarcomatous component and FIGO stage IB and II were statistically negative prognostic factors also concerning OS. At multivariate analysis, only the heterologous sarcomatous component was confirmed to be a statistically significant negative prognostic factor both on PFS (HR 2.362, 95% CI 1.207–4.623, p value = 0.012) and on OS (HR 1.950, 95% CI 1.032–3.684, p = 0.040).ConclusionCarcinomatous and sarcomatous components both played a role in tumor progression and patients’ survival. However, only the sarcomatous component retained a statistical significance at the multivariable model suggesting its preeminent prognostic role in early-stage UCSs.

Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor

BackgroundCarcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts. MethodsSensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment. ResultsOut of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression. ConclusionsElimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.

Correlative Assessment of p53 Immunostaining Patterns and TP53 Mutation Status by Next-Generation Sequencing in High-Grade Endometrial Carcinomas.

TP53 mutations are frequently identified in the copy number-high molecular subgroup of endometrial carcinomas (ECs). P53 immunohistochemistry (IHC) is a widely used surrogate marker reflecting the mutational status of TP53 , and recent reports have shown ~95% concordance between the two methods in ECs. While these results are promising, studies evaluating the correlation between different p53 IHC staining patterns and comprehensive next-generation sequencing results are still limited. We compared the p53 IHC staining patterns, scored as wild-type, diffuse nuclear overexpression, null/complete absence, and cytoplasmic, to next-generation sequencing results reported by FoundationOneCDx in 43 high-grade ECs: 20 serous ECs, 9 mixed ECs with a serous component, 4 carcinosarcomas with a serous component, and 10 grade 3 endometrioid ECs. The concordance of p53 IHC and TP53 mutation status was 100% (43/43) overall, including 100% (33/33) concordance in tumors with a serous component and 100% (10/10) in endometrioid ECs. Among the 35 tumors with aberrant p53 expression the most commonly observed pattern was diffuse nuclear overexpression seen in 69% (24/35), followed by cytoplasmic staining in 17% (6/35), and complete absence of staining (null) in 14% (5/35) of tumors. Of the 6 tumors with cytoplasmic staining, 4 corresponded to missense mutations within the DNA binding domain (V157F in 2 tumors, and S127P and R280S, in 2 tumor each), while 2 corresponded to nonsense mutations in the tetramerization domain (p.E339*). Our results further support that p53 IHC can serve as an accurate predictor of TP53 alterations in ECs to aid the molecular-based tumor classification and the distinction between tumor histotypes, both of which play an important role in the assessment of clinical prognosis and therapeutic decision making. In addition, our data suggest, that the type and position of TP53 mutation may not directly correlate with the observed p53 IHC pattern in all tumors, and that there may be alternative mechanisms for cytoplasmic localization (other than mutations involving the nuclear localization domain), possibly due to conformational changes or posttranslational modifications of the aberrant p53 protein.

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology.

Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options.

A rare mixed ovarian tumor associating borderline endometrioid component and borderline serous component.

A 37-year-old woman was admitted to the department of Gynecology and Obstetrics for management of ovarian cyst, for which a left oophorectomy was performed. The specimen was evaluated then in the department of pathology. On gross examination, the ovarian cyst had a smooth surface and measured 5.5x4.5x 2.5cm. Cut section revealed that the cyst was multilocular, filled with clear fluid and containing several buds. Microscopically, the cyst consisted in a biphasic tumor associating borderline endometrioid component, composed of confluent glands of endometrioid-type epithelium with mild atypical nuclei and borderline serous component. This serous component was made by numerous bulbous, irregularly contoured papillae with fibrous cores and lined by pseudostratified columnar cells with moderate atypia. Immunohistochemical study using WT1 showed positive labeling in the borderline serous component (blue asterisk) and absence of labeling in the borderline endometrioid component (red asterisk). The diagnosis of a mixed ovarian tumor associating a borderline endometrioid component and a borderline serous component was given. A mixed tumor associating two types of ovarian borderline tumors is exceptionally described in the literature. In our case, the presence of a borderline endometrioid component associated with a borderline serous component raises the role of endometriosis in the genesis of ovarian tumors. The pathogenetic transformation from endometriosis to ovarian tumors is not fully understood, but it seems mainly related to many factors: inflammation, oxidative stress, hyperestrogenism, and specific genomic alterations.

ADAGIO: a phase IIb international study of the Wee1 inhibitor adavosertib in women with recurrent or persistent uterine serous carcinoma

BackgroundUterine serous carcinoma is a distinct histologic subtype of endometrial cancer with an aggressive phenotype, poor prognosis, and limited therapeutic options. A previous proof-of-concept phase II trial of the Wee1...

Does the histologic subtype of uterine carcinosarcoma correlate with outcomes?

<h3>Objectives:</h3> To evaluate uterine carcinosarcoma (UCS) by epithelial component subtype and compare clinicopathologic characteristics, recurrence patterns, and survival. <h3>Methods:</h3> We conducted a retrospective medical record review of patients diagnosed with UCS from January 2008 through March 2019 at one institution. Cases of UCS were classified based on carcinoma subtype-endometrioid versus non-endometrioid. Non-endometrioid included serous, clear cell, mixed cell, squamous, poorly differentiated and un-differentiated epithelial components. If a predominant histologic carcinoma subtype was not identified with initial review, the slides were classified by a pathologist. Recurrence sites were pelvic, nodal, or distant. Data are presented as percent, median (interquartile range) or mean ± standard deviation. We compared characteristics between UCS subtypes and calculated hazard ratios (HR) and 95% confidence intervals (CI) for overall survival. <h3>Results:</h3> We identified 77 patients with UCS, 18 (23%) with endometrioid subtype, 58 (75%) with non-endometrioid subtype, and one who could not be classified, as slides were unavailable. Median length of follow-up was 2 years[MRH1]; mean age at diagnosis was 70 years. The cohort was primarily White (66%) and African American (18%). Measured demographic variables, risk factors, symptoms at presentation, surgery, and adjuvant treatments were similar between epithelial subtypes. Most patients underwent surgery (96%) with nodal evaluation in 67%, 77% received chemotherapy, and 51% underwent radiation treatment. Forty percent of patients had mismatch repair protein immunohistochemistry, and 33% of patients with endometrioid subtype had loss of expression of at least one protein compared with 0% in the non-endometrioid group (p=0.02). Of patients with endometrioid subtype, 72% presented in stage I/II compared to only 46% of those with non-endometrioid subtype (p=0.06). The endometrioid subtype was more likely to recur in the pelvis (33%) than non-endometrioid (12%), but of the 32 (46%) patients whose disease recurred, there was no differences in nodal or distant recurrence by subtype. Median overall survival for stage I/II UCS was 6[MRH2] years; patients with stage I/II endometrioid subtype demonstrated poorer overall survival than stage I/II non-endometrioid subtype (HR 3.0, 95% CI 0.98-9.2). Median overall survival for stage III/IV was 2 years; data survival for stage III/IV did not meet assumptions to calculate an HR. <h3>Conclusions:</h3> In this single-institution review of patients with UCS, those with stage I/II endometroid subtype had worse overall survival than those with stage I/II non-endometrioid subtype. Deficiency in mismatch repair protein expression and pelvic site of recurrent disease was more common in endometrioid than non-endometrioid subtypes. These findings suggest that the epithelial subcomponent in UCS has implications for biologic behavior of the disease and therapeutic choice.

The presence of an endometrioid component does not alter the clinicopathologic profile or survival of patients with uterine serous cancer: A gynecologic oncology group (GOG/NRG) study of 934 women

ObjectiveWhile most cases of endometrial cancer can readily be classified as pure endometrioid, pure serous, or another type, others show an apparent mixture of serous and endometrioid components, or indeterminate serous versus endometrioid features. Since serous histology carries a worse prognosis than endometrioid, Gynecologic Oncology Group protocol GOG-8032 was established to examine whether the presence of a non-serous component is a favorable feature in an otherwise serous cancer. Methods934 women with serous cancer were prospectively identified among a larger group enrolled in GOG-0210. Six expert gynecologic pathologists classified each case as pure serous (SER, n=663), mixed serous and endometrioid (SER-EM-M, n=138), or indeterminate serous v. endometrioid (SER-EM-I, n=133) by H&E morphology. Follow-up data from GOG-0210 were analyzed. ResultsThe subgroups did not differ on BMI, race, ethnicity, lymphovascular invasion, cervical invasion, ovary involvement, peritoneal involvement, omental involvement, FIGO stage, or planned adjuvant treatment. SER-EM-M patients were younger (p=0.0001) and less likely to have nodal involvement (p=0.0287). SER patients were less likely to have myoinvasion (p=0.0002), and more likely to have adnexal involvement (p=0.0108). On univariate analysis, age, serous subtype, race, and components of FIGO staging predicted both progression-free and overall survival. On multiple regression, however, serous subtype (SER, SER-EM-M, or SER-EM-I) did not significantly predict survival. ConclusionsThere were few clinicopathologic differences between cases classified as SER, SER-EM-M, and SER-EM-I. Cases with a mixture of serous and endometrioid morphology, as well as cases with morphology indeterminate for serous v. endometrioid type, had the same survival as pure serous cases.NCT#: NCT00340808

PD-L1 and Mismatch Repair Status in Uterine Carcinosarcomas.

Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ≥1 or a TPS score of ≥1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ≥10 or a TPS score of ≥10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas.