Uterine Endometrioid Adenocarcinoma Research Articles

The prognostic impact of substantial lymphovascular space invasion in women with node negative FIGO stage I uterine carcinoma

ObjectiveSubstantial lymphovascular space invasion (LVSI) is an important predictor of lymph node (LN) involvement in women with endometrial carcinoma. We studied the prognostic significance of substantial LVSI in patients with 2009-FIGO stage-I uterine endometrioid adenocarcinoma (EC) who all had pathologic negative nodal evaluation (PNNE). MethodsPathologic specimens were retrieved and LVSI was quantified (focal or substantial) in women with stage-I EC who had a hysterectomy and PNNE. In addition to multivariate analysis (MVA), recurrence-free (RFS), disease-specific (DSS), and overall (OS) survival was compared between women with focal vs. substantial LVSI. Results1052 patients were identified with a median follow-up of 9.7 years. 358 women (34%) received adjuvant radiotherapy. 907 patients (86.2%) had no LVSI, 87 (8.3%) had focal, and 58 (5.5%) had substantial LVSI. Five-year RFS was 93.3% (95% CI: 91.5–95.1), 76.8% (95% CI: 67.2–87.7) and 79.1% (95% CI: 67.6–95.3) for no, focal, and substantial LVSI(p < 0.0001). There was no statistically significant difference in 5-year RFS, DSS, OS, and in the patterns of initial recurrence between women with focal vs substantial LVSI. On MVA with propensity score matching, substantial LVSI was not independently associated with any survival endpoint compared to focal LVSI, albeit both were detrimental when compared to no LVSI. Age ≥ 60 years and higher grade were predictors of worse RFS, DSS, and OS. Additionally, comorbidity burden was an independent predictor for OS. ConclusionsOur results suggest that substantial LVSI does not predict worse survival endpoints or different recurrence patterns in women with stage-I EC with PNNE when compared to focal LVSI.

Clinico-Morphological Features and Immunohistochemical Profile of a Rare Case of Three Synchronous Primary Malignancies in the Female Genital Tract

(1) Background: Synchronous tumors are defined as tumors that occur at the same time, appearing within 2 months, according to the Surveillance Epidemiology and End Results Program, with a frequency of tertiary tumors of 0.5%. The purpose of this presentation is to report a case of three synchronous tumors of the female genital tract, given the fact that it represents a challenge both therapeutically and in demonstrating that the malignant lesions are completely different from each other. (2) Methods: We report the case of a 45 year-old patient diagnosed with three synchronous tumors developed in the genital tract: clear-cell ovarian carcinoma, uterine endometrioid adenocarcinoma, and cervical adenosquamous carcinoma. (3) Results: Total hysterectomy with bilateral anexectomy was performed and accompanied by a biopsy of the greater omentum. The evolution of the patient was favorable during chemotherapy, but she died two weeks after the completion of this treatment, from a cause secondary to the adverse effects determined by it, namely, severe thrombopenia which caused a massive lower digestive hemorrhage. (4) Conclusions: This case demonstrates the maximum importance of the involvement of adjuvant diagnostic techniques, especially when it comes to a diagnostic challenge with direct implications in the subsequent therapy of the patient.

The Prognostic Impact of Substantial Lymphovascular Space Invasion in Women with FIGO Stage I Uterine Endometrioid Carcinoma with Pathologically Negative Nodal Evaluation

Substantiallymphovascular space invasion (LVSI) is an important predictor of lymph node involvement in women with endometrial carcinoma. However, its prognostic significance in women with stage I who had pathologic negative nodal evaluation (PNNE) was not fully evaluated. We aimed to evaluate the prognostic significance of substantial LVSI on recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) in women with FIGO stage I uterine endometrioid adenocarcinoma (EC). Our uterine cancer database was queried for women with stage I EC who had a hysterectomy and PNNE at our institution between 1/1990 and 11/2022. Postoperatively, patients were managed with observation or adjuvant radiation therapy (RT) with pelvic external beam RT or vaginal cuff brachytherapy (VB). Women with synchronous malignancies and those who received adjuvant chemotherapy were excluded. Pathologic specimens were retrieved and LVSI was quantified by Gynecology pathologists (none, focal or substantial). Patients' demographics, surgical and pathologic variables were analyzed. Predictors of RFS, DSS and OS using univariate (UVA) and multivariate analysis (MVA) were studied. One thousand fifty-two patients were identified with a median age of 63 years and median follow-up of 9.7 years. Median number of examined lymph node (LN) were 9 (range 4-18). 907 patients (86.2%) had no LVSI, 87 (8.3%) had focal and 58 (5.5%) had substantial LVSI. In patients with focal LVSI, 32.2% received pelvic RT and 39.1% received VB. In patients with substantial LVSI, 20.7% received pelvic RT and 58.6% received VB.Recurrence was diagnosed in 86 patients (8.2%). While any LVSI was associated with tumor recurrence, there was no significant difference for the site of initial recurrence between patients with focal vs. substantial LVSI. 5-year RFS was 93.3% (95% CI 91.5-95.1), 76.8% (67.2-87.7) and 79.1% (67.6-95.3) for no, focal and substantial LVSI. The 5-year DSS was 97.6% (96.5-98.7), 83.5% (75-93.1), and 90% (81.8-99.9); and 5-year OS was 90.7% (88.7-92.8), 72.8% (62.9-84.2) and 86% (76.2-97.2), respectively. Independent predictors of worse 5-year RFS and DSS include any LVSI, age > 60 years, higher tumor grade. Independent predictors of worse 5- year OS include any LVSI, age > 60, high comorbidity burden, and higher tumor grade. Our large data suggest similar recurrence-free, disease specific and OS for women with stage I uterine endometrioid carcinoma who had pathologically negative nodal evaluation and substantial or focal LVSI. There was no significant difference for the site of initial recurrence between patients with focal or substantial LVSI. Multi-institutional pooled analyses may be needed to validate our results.

Endometrioid Tip Adenokanserde Prognostik Faktörlerin Sağkalıma Etkisi

Objective: The study aims to investigate the prognostic factors in uterine endometrioid adenocarcinoma that affect survival outcomes. &#x0D; Materials and Methods: This retrospective study includes 144 cases which underwent surgical treatment for uterine endometrioid adenocarcinoma. Demographic data and tumour characteristics were evaluated for lymph node metastasis. Stage I and grade 1-2 tumours were divided into lymphadenectomy and non-lymphadenectomy groups, and 5-year survival was assessed. &#x0D; Results: The presence of myometrial invasion of more than 1/2, adnexal metastasis and lymphovascular space invasion were found to be associated with lymph node metastasis (p=0.010 ve 0.019 ve 0.015). In our study, the 5-year survival rate was 87.4%. Survival rate was correlated with age, myometrial invasion, and tumour grade. The 5-year survival rates were 89.8% in lymphadenectomy group and 85.2% in non-lymphadenectomy group, and no statistically significant difference was observed (p=0.575). &#x0D; Conclusion: Myometrial invasion, grade and the age of diagnosis were detected as important prognostic factors of uterine endometrioid adenocarcinomas. We concluded that lymphadenectomy did not increase the survival rate of stage I grade 1-2 endometrioid tumours. Lymphadenectomy may not be performed in stage I grade 1-2 tumours; thus, the morbidities of lymphadenectomy can be avoided.

The Prognostic Significance of the Depth of Cervical Stromal Invasion in Women With FIGO Stage II Uterine Endometrioid Carcinoma.

The objective of this study was to investigate the prognostic significance of the depth of cervical stromal invasion (CSI) in women with FIGO stage II uterine endometrioid adenocarcinoma (EC). Our database of women with EC was quired for patients with stage II EC. Pathologic slides were retrieved and reviewed by gynecologic pathologists to determine cervical stromal thickness and depth of CSI as a percentage of stromal thickness (%CSI). Kaplan-Meier, univariate, and multivariate analyses were used to compare recurrence-free, disease-specific (DSS), and overall survival (OS) between women who had<50% versus ≥50% CSI. Univariate and multivariate analyses were used to assess other prognostic variables associated with survival endpoints. A total of 117 patients were included in our study who had hysterectomy between 1/1990 and 8/2021. Seventy-nine patients (68%) with <50% and 38 (32w%) with ≥50% CSI. After a median follow-up of 131 months, 5-year DSS was significantly worse for women with ≥50% CSI (78% vs. 91%; P =0.04). However, %CSI was not an independent predictor for any of the studied survival endpoints. Independent predictors of worse 5-year recurrence-free survival and DSS included FIGO grade 3 tumors ( P =0.02) and the presence of lymphovascular space invasion ( P =0.03). Grade 3 tumors were the only independent predictor of worse 5-year OS ( P =0.02). Our results suggest that deep CSI is not an independent prognostic factor for survival endpoints in women with stage II uterine endometroid adenocarcinoma. The lack of independent prognostic significance of the depth CSI needs to be validated in a multi-institutional analysis.

Development of Adverse Outcome Pathways relevant for the identification of substances having endocrine disruptors properties

This report is the outcome of an EFSA procurement (NP/EFSA/PREV/2020/01) which aims at contributing to the development of adverse outcome pathways (AOPs) to be integrated in a network addressing uterine adenocarcinoma in mammals. The outcome is intended to support the identification of substances with endocrine disruptor mode of action. For this specific purpose, an evidence-based approach methodology was adopted. Available evidence was systematically mapped from the literature to identify Molecular Initiating Events (MIEs) and Key Events (KEs) linked to adverse outcome (AO) “uterine endometrioid adenocarcinoma” independently from prototypical stressors, by means of: 1. a priori defined search strategies initially addressing the AO and biologically plausible MIEs, 2. application of machine learning technique (Topic modelling) that automatically analyzes text data to identify biologically plausible KERs, 3. systematic literature review and critical appraisal of prioritized evidence, taking into account human, in vivo and in vitro studies. Estradiol and tamoxifen, two recognized human risk factors for endometrioid adenocarcinoma, were used as tool chemical compounds to empirically support the response and temporal concordance of the identified key event relationships (KERs). All evidence has been then integrated by means of the AOP conceptual network. An evidence-based AOP starting from activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma via epigenetic modulation was postulated.

A Technical Glitch or Whispers of Changing Epidemiology of HPV Negative Carcinoma Cervix? An Exploratory Study

<h3>Purpose/Objective(s)</h3> To study the prevalence of HPV negative Carcinoma Cervix (CC) and its prognostic impact on survival. <h3>Materials/Methods</h3> Data of all CC who were treated with concurrent chemoradiotherapy followed by brachytherapy from 1^st Jan 2014 to 31^st December 2018 was retrieved. A total of 79 patients whose biopsy samples were available for genotyping were included in the study. DNA was extracted from cervical cell suspensions using Qiagen DSP virus kit (Ref-60704). The genotyping was done using 3B Black Bio TRUPCR HPV HR with 16/18 genotyping kit which is based on amplification of E6/E7 region by primers and probes specific for detection of 14 HPV subtypes. All procedures were followed as per instructions on the kit insert. Survival analysis was done using Kaplan Meier survival curves with log rank test used to compare the factors with respect to Overall survival (OS) and recurrence free survival (RFS). Statistical software was used for all statistical analyses. <h3>Results</h3> Seventy one percent (56/79) of the patients were HPV positive whereas 29% (23/76) were HPV negative. Out of the HPV positive patients, P16 positivity was the most predominant genotype with 73.2% (41/56) patients testing positive for it followed by P18 (14.3%). The remaining 12.5% of patients tested positive for HPV 31,35,51,52,56,58,59 and 68 subtypes. The unusual high rates of HPV negativity could be due to cervical cancers evolving independent of high-risk HPV, loss of expression of HPV, misclassification of cancers and inherent false negativity rates of the methods used for testing of HPV. All these factors were kept to a minimum by ensuring that the low and intermediate risk subtypes of HPV responsible were also tested for, the misclassification of uterine endometrioid adenocarcinoma or metastasis as CC was minimized by independent review of two experienced pathologists and testing related errors were kept at bare minimum by following the standard procedures provided by the manufacturers. Based on the extant literature, the combined false negativity rate of all the above factors, combined together, was approximately 7-8%, leaving an unexplained 21-22% of the HPV negative prevalence in the cohort. This could well be due to the rising trend of HPV negative carcinoma cervix which need a nuanced look on a broader basis as it might lead to a readjustment of our tactics in prevention and management of CC. The estimated 5-year OS of the HPV positive and HPV negative population within the study group was 84.5% and 82.6% respectively (P value=0.425). Median overall survival was not reached and needs a longer follow-up. <h3>Conclusion</h3> The HPV negativity rates among patients of CC in our study cohort were unusually high (29%). Detailed and systematic perusal of possible factors contributing to such high rates still left an uncharted void of approximately 21% which might be an early pointer towards rising trend of HPV negative CC.

The Prognostic Significance of the Depth of Cervical Stromal Invasion in Women with FIGO Stage II Uterine Endometrioid Carcinoma

<h3>Purpose/Objective(s)</h3> To explore the prognostic significance of the depth of cervical stromal invasion (CSI) on survival endpoints in women with FIGO stage II uterine endometrioid adenocarcinoma. <h3>Materials/Methods</h3> A total of 117 patients were included in this retrospective review. Between 1990 and 2021, all patients with FIGO stage II endometrial cancer (EC) underwent hysterectomy and oophorectomy at our institution, with or without lymph node dissection. Patients with synchronous ovarian or breast cancer, as well as those who had undergone adjuvant systemic chemotherapy for EC, were excluded from the study. Pathologic slides were retrieved for these patients and were reviewed by a gynecologic pathologist to determine stromal thickness and the depth of CSI. The depth of CSI was then measured as a percentage of invasion (% CSI) and used in the analysis as a continuous or dichotomous variable (< 50% vs > = 50%). Patients' demographics, pathologic, and treatment characteristics were analyzed using univariate and multivariate analysis to calculate recurrence-free (RFS) and disease-specific (DSS) rates. <h3>Results</h3> The median age for the study cohort was 65 years (range, 34–96), and the median follow-up was 131 months (range, 9–334). A total of 90 patients (77%) had lymph node dissection, with a median of 8 examined lymph nodes (range 0-18). Adjuvant radiation therapy (RT) with pelvic or vaginal cuff HDR brachytherapy, or a combination of the two, was completed in 92 patients (79 percent). The median % CSI was 27% (range, 1-100) with 68% of patients having ≥ 50% CSI. While there was a trend for a worse 5-year RFS and DSS for women with ≥ 50% CSI (69% vs. 83%, p = 0.093) and (78% vs. 91%, p = 0.034), respectively, the depth of CSI was not statistically significant as an independent predictor of 5-year RFS, DSS, or OS. The depth of CSI was not associated with a difference in the recurrence pattern (vaginal cuff, pelvic, paraaortic, or distant). In multivariate analysis, FIGO grade was the only predictor of 5-year OS. FIGO grade and the presence of lympho-vascular space invasion (LVSI) were independent predictors of 5-year RFS and DSS. <h3>Conclusion</h3> Deep cervical stromal invasion does not appear to be an independent predictive factor for survival endpoints in women with stage II uterine endometroid cancer, according to our findings. The presence of LVSI and tumor grade were both independent predictors of recurrence-free and disease-specific survival. Pooled data analysis may be needed to validate our study findings.

Pan-Cancer Prognostic Role and Targeting Potential of the Estrogen-Progesterone Axis.

IntroductionEstrogen receptors (ESRs) and progesterone receptors (PGRs) are associated with the development and progression of various tumors. The feasibility of ESRs and PGRs as prognostic markers and therapeutic targets for multiple cancers was evaluated via pan-cancer analysis.MethodsThe pan-cancer mRNA expression levels, genetic variations, and prognostic values of ESR1, ESR2, and PGR were analyzed using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and cBioPortal. The expression levels of ERa, ERb, and PGR proteins were detected by immunohistochemical staining using paraffin-embedded tissue specimens of ovarian serous cystadenocarcinoma (OV) and uterine endometrioid adenocarcinoma (UTEA). Correlation between immunomodulators and immune cells was determined based on the Tumor and Immune System Interaction Database (TISIDB).Results ESR1, ESR2, and PGR mRNAs were found to be differentially expressed in different cancer types, and were associated with tumor progression and clinical prognosis. ERa, ERb, and PGR proteins were further determined to be significantly differentially expressed in OV and UTEA via immunohistochemical staining. The expression of ERa protein was positively correlated with a high tumor stage, whereas the expression of PGR protein was conversely associated with a high tumor stage in patients with OV. In patients with UTEA, the expression levels of both ERa and PGR proteins were conversely associated with tumor grade and stage. In addition, the expression levels of ESR1, ESR2, and PGR mRNAs were significantly associated with the expression of immunomodulators and immune cells.Conclusion ESR1, ESR2, and PGR are potential prognostic markers and therapeutic targets, as well as important factors for the prediction, evaluation, and individualized treatment in several cancer types.

Abstract 2432: Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting

Abstract Background: Signal transducer and activator of transcription 3 (STAT3) activation promotes tumor cell survival, immune evasion, metastasis, and drug resistance in PARP inhibitors and platinum-based chemotherapy. Objective: Based on our in-vitro findings of the tumoricidal potential of STAT3 inhibition in BRCAwild-type and PARP inhibitor-resistant tumor cells, we sought to evaluate whether ovarian and uterine cancer patients with somatic mutations in the STAT3 activation pathway had improved overall survival (OS) compared to those with intact STAT3 activation pathway-related genes. Method: We induced Olaparib resistance in BRCAwild-type ovarian cancer cell lines (OVCAR8 and A2780) and treated both parental and PARP inhibitor-resistant cell lines with various STAT3 inhibitors. We then attempted to establish clinical correlations of our in-vitro studies and queried the Cancer Genome Atlas (TCGA) Pan-Cancer Atlas for uterine and ovarian cancers. OS in patients with somatic mutations in the STAT3 gene and/or associated STAT3 activation genes (IL6ST, GNAS, JAK1, JAK2) was compared to OS in patients with intact STAT3 pathway-related genes. Kaplan-Meier survival curves were compared using the log-rank test. Results: In-vitro, STAT3 inhibition demonstrated potent, tumoricidal propensity in all cell lines (EC50: 0.34uM-0.46uM) including A2780parental, A2780parpi-resistant, OVCAR8parental, and OVCAR8parpi-resistant. Clinically, 1,154 total patients were identified in TCGA, including 571 high-grade serous ovarian carcinoma, 397 uterine endometrioid adenocarcinomas, 109 uterine serous carcinoma/uterine papillary serous carcinomas, 56 uterine carcinosarcomas/uterine malignant mixed Mullerian tumors, and 21 uterine mixed endometrial carcinomas. When pooling all uterine and ovarian cancer patients, median survival (MS) was 52 months (0-185) in patients with intact STAT3 (n=1,007) compared to not reached (NR, 0-225) in the STAT3 mutated group (n=147) with a Hazard Ratio (HR) of 0.25 and Confidence Interval (CI) 0.20-0.32 (p&amp;lt;0.001). In ovarian cancer patients, MS was 45 months (0-180) in patients with intact STAT3 (n=551) compared to 95 months (0-145) in the STAT3 mutated group (n=20) with a HR of 0.48 and CI 0.29-0.80 (p=0.038). In uterine cancer patients, MS was 112 months (0-185) in patients with intact STAT3 (n=456) compared to NR (0-225) in the STAT3 mutated group (n=127) with a HR of 0.40 and CI 0.25-0.64 (p=0.003). Conclusion: Pharmacologic and genetic (siRNA) inhibition of the STAT3 activation pathway killed PARP inhibitor-resistant ovarian cancer cells in-vitro. Clinically, somatic mutations in the STAT3 activation pathway were associated with improved OS in both ovarian and uterine cancer. These findings provide a rationale for the therapeutic targeting of this pathway in gynecologic malignancies. Citation Format: Adrian Kohut, Antons Martincuks, Thanh Dellinger, Hua Yu, Lorna Rodriguez-Rodriguez. Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2432.

FIGO Grade 3 Endometrioid Adenocarcinomas With Diffusely Aberrant β-Catenin Expression: An Aggressive Subset Resembling Cutaneous Pilomatrix Carcinomas.

Uterine endometrioid adenocarcinomas are known for their morphologic plasticity. In addition to a multiplicity of metaplasias, uterine endometrioid adenocarcinomas may also undergo high-grade divergent differentiation in the form of high-grade neuroendocrine carcinoma, neuroectodermal differentiation or carcinosarcoma; others may dedifferentiate completely. Here we describe 5 cases of uterine endometrioid adenocarcinomas with high-grade divergent differentiation showing a striking morphologic and immunophenotypic resemblance to cutaneous pilomatrix carcinoma. Specifically, the high-grade component in all cases exhibited solid, basaloid morphology with conspicuous tumor cell necrosis and the presence of shadow cells, accompanied by diffusely aberrant (nuclear and cytoplasmic) β-catenin expression as well as variably diffuse CDX2 expression. In addition, the high-grade component in all cases showed loss of ER and PAX8 expression, retained MMR expression, wild-type p53 expression, patchy p16 expression, and diffusely positive cytokeratin expression (AE1/AE3 and CK7); at least focal neuroendocrine marker expression was present in all cases. CK20 was negative in all cases, with the exception of very focal staining in a single case (2% of tumor cells). All 5 of our tumors had at least a focal conventional FIGO grade 1 component. In all 4 cases tested, the low-grade component retained both PAX8 and ER expression and had, at best, focally aberrant β-catenin expression. Two of our cases had molecular analysis performed and both harbored mutations in exon 3 of CTNNB1 as expected; molecular analysis also revealed that both cases lacked POLE or TP53 mutations and showed no microsatellite instability. The tumors in this series were uniformly aggressive. Four of the 5 patients in our cohort had available follow-up information; of these, 3/4 died of their disease within 14 mo of diagnosis and the fourth patient had distant metastatic disease at presentation and is alive with disease 1 mo following diagnosis. The 1 patient without follow-up information also had distant metastatic disease at presentation and was lost to follow-up 17 mo later. The cases described in this series (1) represent a highly aggressive CTNNB1-mutated subset of the "no specific molecular profile" category of endometrioid adenocarcinomas; (2) illustrate a form of high-grade divergent differentiation resembling cutaneous pilomatrix carcinoma already described in carcinomas at other anatomic sites; and (3) underscore the difficulty in recognizing this phenotype at distant metastatic sites, which are frequent even at the time of presentation, given the consistent loss of ER and PAX8 expression and concurrent CDX2 expression.

Nuclear Beta-Catenin Expression in Endometrioid Intraepithelial Neoplasia (Atypical Hyperplasia) Does Not Predict Carcinoma on Subsequent Hysterectomy

Beta-catenin (BC) mutations are associated with a high risk of recurrence in otherwise low-grade, early-stage uterine endometrioid adenocarcinomas. Recent literature suggests nuclear BC expression by immunohistochemistry is highly sensitive and specific for BC mutations. The significance of BC expression in endometrioid intraepithelial neoplasia (EIN/atypical hyperplasia) and its relationship to altered differentiation patterns in EIN has yet to be fully explored. Cases meeting current diagnostic criteria for EIN based on H&E examination were obtained from 2 institutions (years 1999-2014). Patterns of altered differentiation (eg, tubal, squamous morular metaplasia, mucinous, secretory) were noted. Representative blocks were stained for BC, and expression patterns recorded. Follow-up and demographic data was obtained from the electronic medical record. Ninety-six cases were included (84 biopsies, 12 hysterectomies). BC nuclear expression was identified in 41 cases (42.7%), with 33 of 41 demonstrating foci of nonmorular BC staining. BC staining in any component of EIN was not significantly associated with the presence of carcinoma on subsequent hysterectomy (P=0.79). When restricting to nonmorular BC, the results were the same (P=0.56). Cases with tubal differentiation were significantly less likely to demonstrate nonmorular BC than cases with no specific pattern of differentiation (P<0.01). EIN frequently demonstrates BC nuclear positivity, especially in cases without tubal differentiation. BC nuclear expression in EIN does not appear to be associated with an increased likelihood of carcinoma on subsequent hysterectomy. Our results do not support routine use of BC immunohistochemistry as a prognostic biomarker in cases of EIN.

Small Cell Carcinoma of the Ovary: Clinicopathologic and Immunohistochemical Analysis of 7 New Cases of a Rare Malignancy

Small cell carcinoma of ovary (SCCO) is extremely rare. Two types of SCCO are recognized, the pulmonary type (SCCOPT) and the hypercalcemic type (SCCOHT). Establishing an accurate diagnosis is challenging, owing to its rarity and paucity of data describing the distinctive histopathologic and immunohistochemical (IHC) features. This was a retrospective study conducted over a period of 4 years. All cases reported as SCCO on histopathology were retrieved. All the available clinical, histopathological, and IHC features were studied in detail. A total of 7 cases of SCCO were diagnosed during the study period. There were 4 cases of SCCOPT and 3 cases of SCCOHT and with mean age of 57.25 and 22 years, respectively. All the cases presented as stage IV disease. Among the SCCOPT cases, 3 showed bilateral involvement with 1 showing concurrent uterine endometrioid adenocarcinoma. Microscopy revealed small hyperchromatic cells with brisk mitosis and multifocal necrosis. On IHC, these were consistently positive for chromogranin, CD56, and synaptophysin. All the SCCOHT cases showed unilateral involvement. Microscopically, in addition to small hyperchromatic cells, larger "rhabdoid" tumor cells were also seen. On IHC, chromogranin was negative, with positivity for vimentin and epithelial membrane antigen. The expression of SMARCA4/BRG1 was lost while SMARCB1/INI1 was retained in all cases. All of these patients developed recurrence and died due to disease progression despite treatment. SCCO is an extremely infrequent ovarian malignancy with poor prognosis. Knowledge about its characteristic features is important for accurate tissue diagnosis and appropriate management.

Differentiation of endometrial adenocarcinoma from adenocarcinoma of cervix using kinetic parameters derived from DCE-MRI

PurposeThis prospective study aimed to investigate the value of kinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in differentiating uterine endometrioid adenocarcinoma (EAC) from adenocarcinoma of cervix (AdC). MethodsSeventy-five newly diagnosed patients with distinctive pathology underwent DCE-MRI. Observers independently calculated the tumor diameters and DCE-MRI parameters using both population and individual-based arterial input function (AIF). Inter-observer consistency was evaluated, and a comparative analysis between EAC (n = 47) and AdC (n = 28) was performed. Regression analysis was used to select parameters that best distinguished EAC from AdC, and to generate predictive models. Receiver operating characteristic curve (ROC) was applied to calculate the diagnostic efficiency of single parameter and the predictive models. ResultsInter-observer consistency was excellent (intra-class correlation [ICC] = 0.902−0.981), especially when calculated via population AIF with relatively higher ICC and smaller SD on Bland-Altman plot. Tumor diameters were not correlated with tumor types. All the DCE-MRI parameters were lower in EAC compared to AdC, except Kep by population AIF and TTP by both sets of AIFs. The statistical parameters were Ve, Maxslop, and Maxconc by population AIF, and Maxslop and Ktrans by individual AIF included in the predictive models, respectively. The two predictive models with combined parameters showed improved diagnostic efficiency in differentiating these two diseases compared with a single parameter. ConclusionDCE-MRI can quantitatively evaluate the perfusion difference between EAC and AdC, thus improving the identification of uterine adenocarcinoma with uncertain biopsy pathology.

Undifferentiated Uterine Sarcoma with Endometrioid Adenocarcinoma of the Uterus: A Rare Collision Tumor

Collision tumors consist of two histologically different tumors in the same organ independently of each other. Collision tumors of the esophagus, stomach, colon, lung, skin, thyroid gland, breast, uterus and ovary have been reported. Here, we report a case of a collision tumor of the uterine endometrioid adenocarcinoma and undifferentiated uterine sarcoma. Tumors with these features are not as aggressive as malignant mixed mullerian tumors (MMMTs) and it is important to distinguish them from MMMTs.

Are Uterine Grade 3 Endometrioid Adenocarcinoma and Carcinosarcoma Really Clinically Similar?

The aim of this study was to compare the clinical characteristics and outcomes of the cases with uterine high-grade endometrioid adenocarcinoma (HGEAC) and uterine carcinosarcoma (UCS). A total of 141 patients were included in this study. Of them, 61 cases had uterine HGEAC (group 1) and 80 had UCS (group 2). Both groups were compared in terms of clinical and pathological characteristics including age, stage, initial symptom, surgical approach, myometrial invasion, lymphovascular space invasion (LVSI), lymph node invasion, adjuvant therapy, and survival. The Kaplan–Meier and Cox proportional hazards models were used to compare the outcomes and prognostic factors. There were no statistically significant differences between the groups with regard to age, nulliparity, menopausal status, and the main initial symptom. Both groups were similar in terms of stage, depth of myometrial invasion, and lymph node metastasis. Lymphadenectomy was performed in 74% and 91% of the cases in group 1 and group 2, respectively (p < 0.001). LVSI was found to be more frequent in group 1 (p = 0.032); however, in group 2, positive cytology was more common (p = 0.008). Chemotherapy was the main adjuvant therapy for UCS, while radiotherapy was the main adjuvant therapy for HGEAC. There was no difference between the groups in terms of disease-free survival (DFS); however, overall survival (OS) was found to be longer in group 1 (p = 0.029). Histopathologic type and LVSI were determined as independent predictive factors for OS. UCSs are clinically more aggressive than HGEAC and should be considered as a separate group of tumors.

Clonal analysis revealed functional heterogeneity in cancer stem-like cell phenotypes in uterine endometrioid adenocarcinoma

Uterine endometrial carcinoma is one of the common cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are tumorigenic and are resistant to treatments, thus they are focused as treatment targets. However, the heterogeneity of CSCs/CICs is still elusive, and we therefore analyzed CSCs/CICs at the clonal level. We previously established sphere-cultured CSCs/CICs from primary human uterine endometrial carcinoma, and we isolated several clones from CSCs/CICs in this study. Interestingly, we established two types of clones based on the growth pattern. The clones were termed sphere clones (S clones) and leukemia-like clones (LL clones). Functional analysis revealed that S clones are resistant to chemotherapy, whereas LL clones are sensitive to chemotherapy. On the other hand, S clones are less tumorigenic, while LL clones are highly tumorigenic. Transcriptome analysis using serial analysis of gene expression sequencing (SAGE-Seq) revealed distinctive gene expression profiles in S clone cells and LL clone cells. The results indicate that CSCs/CICs are composed of functionally heterogenic subpopulations including highly tumorigenic clones and treatment-resistant clones and that the characteristics of CSCs/CICs might be determined by the characteristics of different clones that compose CSCs/CICs.

Discordant loss of mismatch repair proteins in advanced endometrial endometrioid carcinoma compared to paired primary uterine tumors

ObjectiveA subset of endometrial cancer is characterized by deficiencies in the mismatch repair (MMR) pathway. MMR testing is a well-established tool to screen for Lynch syndrome, but has also become a companion diagnostic test for immunotherapy. We compared the MMR status of primary and paired metastatic endometrial cancer to determine whether MMR deficiency can occur specifically in advanced endometrial cancer compared to primary tumor. MethodsMatched primary uterine and metastatic endometrioid adenocarcinoma from 2009 to 2018 at our institution were identified. PMS2 and MSH6 protein expression in metastatic and matched primary tumor was assessed using clinically validated immunohistochemistry methods for Lynch syndrome screening. MLH1 promoter hypermethylation and microsatellite instability (MSI) were performed in discordant cases. Results29 patients were identified with paired primary endometrial endometrioid adenocarcinoma and metastasis or recurrence after the original hysterectomy. Fourteen of 29 cases (48.2%, 14/29) were found to be MMR deficient at the metastatic or recurrent site. Two patients (6.9%, 2/29) showed discordant MMR status with PMS2 protein loss at the metastatic sites and intact expression in the primary uterine tumors. Both discordant cases exhibited abnormal subclonal loss at primary site and MLH1 promoter hypermethylation. High levels of microsatellite instability (MSI-H) was confirmed in one discordant metastatic site. ConclusionAdvanced endometrial cancer can rarely (~7%) show somatic loss of MMR protein expression in recurrent or metastatic sites compared to matched paired primary tumor. MMR testing of recurrent or metastasis should be considered for guiding immunotherapy if primary uterine tumor exhibits abnormal subclonal MMR loss.

Primary Adenocarcinoma of the Uterine Cervix: Classification and Grading

Abstract Cervical adenocarcinomas are a group of malignancies with several distinct histologic tumor types, which include endocervical usual type, endometrioid, intestinal, villoglandular, gastric, signet ring, serous, clear cell, and mesonephric. Diagnosis of cervical adenocarcinoma, in particular early diagnosis, and classification of the tumor type may pose a significant challenge. The goal of this article is to review the current classification, diagnostic criteria, adjunct markers, and differential diagnosis of various subtypes of cervical adenocarcinomas. The article presents up-to-date summary of such problematic issues as differentiating glandular tumors from benign mimics, differentiating early invasive lesions from adenocarcinoma in situ, determining the tumor type, and, finally, differentiating primary cervical adenocarcinoma from uterine endometrioid adenocarcinoma. Discussion of human papillomavirus detection in different tumor types is provided.

Cervical Adenocarcinoma: Diagnosis of Human Papillomavirus-Positive and Human Papillomavirus-Negative Tumors.

- Cervical adenocarcinomas span a diverse group of tumors with several distinct histologic tumor types, which include endocervical, endometrioid, intestinal, villoglandular, gastric, signet ring, serous, clear cell, and mesonephric. Diagnosis of cervical adenocarcinoma, especially early diagnosis, poses a significant challenge. - To review the pathogenesis, diagnostic criteria, immunohistochemical markers, and differential diagnosis of various subtypes of human papillomavirus (HPV)-positive and HPV-negative cervical adenocarcinomas. The paper presents a concise summary of the issues that may be particularly difficult in histopathologic diagnosis, such as differentiating neoplastic lesions from benign mimics, determining the tumor type, differentiating early invasive lesions from adenocarcinoma in situ, measuring the depth of invasion, and, finally, differentiating primary cervical adenocarcinoma from uterine endometrioid adenocarcinoma and tumors metastatic from other primary sites. - The study employed a PubMed search of recently published reports. - Early detection of HPV-positive tumor types may be aided with the expansion of HPV testing; however, early diagnosis of HPV-negative cervical adenocarcinomas will continue to pose a challenge and may require the development of additional molecular testing techniques.