Maternal Reassurance, Satisfaction, and Anxiety after First-Trimester Screening for Aneuploidies: Comparison between Contingent Screening and Universal Cell-Free DNA Testing.

BACKGROUND: This study aims to evaluate maternal reassurance, satisfaction, and anxiety after two different strategies for the first-trimester screening for aneuploidies. METHODS: Patients between 11 + 3 and 13 + 6 weeks of gestation attending the first-trimester screening at Department of Mother and Child, University Hospital Federico II, Naples, Italy have been recruited and randomly allocated to contingent screening or universal cell-free fetal DNA testing (cffDNA). Questionnaires to measure reassurance, satisfaction, and anxiety have been filled twice: (Q1) after randomization and (Q2) after receiving results. Anxiety was measured by an Italian-version short form of the state scale of the Spielberger State-Trait Anxiety Inventory (STAI); child-related anxiety was measured by the 11-item Pregnancy-Related Anxiety Questionnaire-Revised Regardless of Parity (PRAQ-R2 scale); fear of bearing a physically or mentally handicapped child was measured considering only four items (item 4, 9, 10, and 11) of the PRAQ-R2 scale. RESULTS: 431 patients were recruited: 205 (49%) were randomized in the contingent screening arm, 226 (51%) in the cfDNA arm. Maternal reassurance, satisfaction, and anxiety were not different in the two groups. CONCLUSION: A contingent screening for aneuploidies in the first trimester seems able to ensure the same maternal reassurance and satisfaction as a cfDNA analysis in the low-risk population and to not affect maternal anxiety.

Ovarian endometrioid carcinoma with a sex cord-like pattern: a morphological, immunohistochemical, and molecular analysis.

Sex cord-like endometrioid carcinoma (SCLEC) is an uncommon entity which may constitute a diagnostic challenge. This study aimed to perform a clinicopathological, immunohistochemical, and molecular reappraisal of ovarian SCLEC. Consecutive ovarian SCLECs cases from a single institution were reviewed during a 13-year period. Twenty-three immunohistochemical markers were tested; 10 genes were analyzed by next-generation sequencing. Nine cases of ovarian SCLEC were identified. Mean patient age was 65.7 years; three cases showed extraovarian extension. Architectural pattern included sertoliform (n = 2), granulosa-like (n = 2), and mixed granulosa-like/sertoliform (n = 5). Eosinophilic changes accompanied by increased nuclear atypia were observed in four tumors. Endometrioid features (glands, squamous/morular differentiation) were observed in six cases. Most tumors were positive for cytokeratin-7 (8/9), EMA (9/9), estrogen and progesterone receptor (9/9), CD10 (7/9, including a luminal pattern reminiscent of mesonephric neoplasms), nuclear ß-catenin (8/9), and CDX2 (8/9). A minority of cases showed block-type p16 pattern (2/9), PAX8-positivity (3/9), and non-diffuse positivity for WT1 (1/9), inhibin (1/9), chromogranin (1/9), and synaptophysin (2/9). All cases were negative for GATA3, TTF1, calretinin, and SF1. Ki67 range was 15-90%. Six cases showed CTNNB1 exon 3 mutation. Eight cases were of "no specific molecular profile" (NSMP) and one was p53-abnormal. In conclusion, SCLECs frequently exhibit a mixed sertoliform/granulosa-like architecture and express epithelial markers, hormone receptors, nuclear ß-catenin, and CDX2, with luminal CD10 positivity and CTNNB1 mutations. PAX8 expression is often lost, while other mesonephric, sex cord, and neuroendocrine markers are negative.

Prognostic Value of Mandard's Tumor Regression Grade (TRG) in Post Chemo-Radiotherapy Cervical Cancer.

In locally advanced cervical cancer (LACC), definitive chemo-radiotherapy is the standard treatment, but chemo-radiotherapy followed by surgery could be an alternative choice in selected patients. We enrolled 244 patients affected by LACC and treated with CT-RT followed by surgery in order to assess the prognostic role of the histological response using the Mandard scoring system. Results: A complete pathological response (TRG 0) was observed in 118 patients (48.4%), rare residual cancer cells (TRG2) were found in 49 cases (20.1%), increased number of cancer cells but fibrosis still predominating (TRG3) in 35 cases (14.3%), and 42 (17.2%) were classified as non-responders (TRG4-5). TRG was significantly associated with both OS (p < 0.001) and PFS (p < 0.001). The survival curves highlighted two main prognostic groups: TRG1-TRG2 and TRG3-TRG4-5. Main responders (TRG1-2) showed a 92% 5-year overall survival (5y-OS) and a 75% 5-year disease free survival (5y-DFS). Minor or no responders showed a 48% 5y-OS and a 39% 5y-DFS. The two-tiered TRG was independently associated with both DFS and OS in Cox regression analysis. Conclusion. We showed that Mandard TRG is an independent prognostic factor in post-CT/RT LACC, with potential benefits in defining post-treatment adjuvant therapy.

Ectrodactyly-ectodermal dysplasia-clefting syndrome. Prenatal prospective ultrasound diagnosis.

OBJECTIVE: Prenatal diagnosis of the Ectrodactyly-Ectodermal dysplasia-clefting (EEC) syndrome has been based upon the detection of ectrodactyly, in association with facial clefting and/or positive family history. Our aim is to describe other ultrasonographic features indicating the presuntive diagnosis, regardless of genetic diagnosis, especially in cases of negative family history. MATERIALS AND METHODS: A case report and a review of the literature was assessed. RESULTS: Our case report showed a singleton foetus "lobster claw" deformities of hands and feet. Paternal history revealed bilateral agenesia of two fingers. Through literature, 15 case reports of prenatal diagnosis of EEC syndrome were found, 14 of which were eligible for our systematic review. The 33% of cases (5/15) had a familiar history of EEC, thus, we found one case of consanguinity of parents. Anomalies EEC-related were recognized in the 40% of cases (6/15). An association with genitourinary anomalies was found in 30% (5/15) of them. CONCLUSIONS: A strong suspicion of final diagnosis of EEC may be done in the presence of ectrodactyly, facial clefting and urinary malformation especially in cases of negative family history. More attention should be given to a genetic counseling, especially to understand a possible relation to other genetic syndromes.

BDNF and NGF Expression in Preneoplastic Cervical Disease According to HIV Status.

BACKGROUND: Neurotrophins, such as BDNF and NGF, are overexpressed in tumor cells in cervical cancer, and HIV infection is associated with the upregulation of neurotrophin expression. Therefore, we aimed to investigate whether BDNF and NGF are overexpressed in preneoplastic cervical disease from HIV-infected women. METHODS: Women with preneoplastic cervical lesions (cervical intraepithelial neoplasia grade 2 or 3) were prospectively enrolled and grouped according to their HIV status. Samples from Loop Electrosurgical Excision Procedure (LEEP) for suspected cervical cancer were obtained, and immunohistochemistry was performed to evaluate BDNF and NGF expression. RESULTS: We included in our analysis 12 HIV-infected patients who were matched with 23 HIV-negative patients as a control group. Immunohistochemistry analysis showed that BDNF expression was significantly higher in cervical preneoplastic lesions from HIV-positive women than in the lesions from the control group. In particular, BDNF was expressed in 8/12 HIV-positive patients and 7/23 HIV-negative patients (66.7% vs. 30.4%, χ2 = 4.227; p = 0.040). NGF expression was not significantly higher in cervical preneoplastic lesions from HIV-positive women compared with that in the lesions from the control group. In particular, NGF was expressed in 8/12 HIV-positive patients and in 12/23 HIV-negative patients (66.7% vs. 52.2% χ2 = 0.676; p = 0.411). Logistic regression analysis showed that the HIV status is an independent predictor of BDNF expression in pre-invasive preneoplastic cervical disease when considered alone (crude OR 4.6, 95% CI 0.027-20.347; p = 0.046) and when analyzed with other co-factors (adjusted OR 6.786, 95% CI 1.084-42.476; p = 0.041). CONCLUSIONS: In preneoplastic cervical disease, BDNF expression is higher in HIV-infected women than in non-infected controls, and this is independent of the clinical features of the patients and from the presence of the HPV-HR genotype. BDNF can play a key role as a link between the pathways by which HIV and HPV interact to accelerate cervical cancer progression and invasion. These data can be useful to better understand the role of neurotrophins in the cancerogenesis of cervical cancer and the possible therapeutic strategies to improve disease outcomes.

Corded and hyalinized endometrioid carcinoma: Summary of clinical, histological, immunohistochemical and molecular data.

Corded and hyalinized endometrioid carcinoma (CHEC) represents a potential pitfall for pathologists. This study aimed to provide a complete overview of all clinicopathological and molecular features of CHEC. Electronic databases were searched for all published series of CHEC. Clinical, histological, immunohistochemical and molecular data about CHEC were extracted and pooled. Six studies with 62 patients were identified; mean age was 49.8 years (range 19-83). Most cases showed FIGO stage I (68%), low grade (87.5%), and a favorable outcome (78.4%), with "no specific molecular profile" (NSMP). A subset of cases showed high-grade features (12.5%), p53 abnormalities (11.1%) or mismatch repair (MMR) deficiency (20%) and occurred at an older age (mean age>60 years). Common features of CHEC were: superficial localization of the corded component (88.6%), squamous/morular differentiation (82.5%), nuclear ß-catenin accumulation (92%), partial/total loss of CKAE1/AE3 (88.9%), estrogen receptor (95.7%) and e-cadherin (100%), stromal changes such as myxoid (38.5%), osteoid (24%) and chondroid (4.5%), CTNNB1 mutations (57.9%), and POLE-wild-type (100%); 24.4% of cases showed lymphovascular space invasion. A minority of cases (16.2%) showed poor outcome despite a low-grade, NSMP phenotype; the molecular basis for the aggressiveness of these cases is still undefined. Further studies are necessary in this field.

High-grade serous ovarian carcinoma with a sertoliform pattern associated with BRCA mutation: a clinicopathological and molecular analysis.

Herein, we report a clinicopathological and molecular analysis of a case of tubo-ovarian high-grade serous carcinoma (HGSC) with a sertoliform pattern. A 45-year-old woman underwent surgery due to an advanced bilateral adnexal carcinoma with peritoneal and appendiceal metastases. Histological examination revealed an HGSC exhibiting a distinct sertoliform component. Such component showed diffuse PAX8, p53 (mutation-type), and p16 (block-type) expression, increased vimentin and decreased WT1 expression compared to the conventional HGSC component, membrane ß-catenin positivity, heterogeneous estrogen, and progesterone positivity, and retained PTEN and mismatch repair expression and negativity for GATA3, TTF1, inhibin, calretinin, CD10, CDX2, chromogranin, and synaptophysin. Molecular analysis showed a germline BRCA2 mutation; no mutations were detected in POLE, POLD1, MLH1, MSH2, MSH6, PMS2, APC, CTNNB1, MUTYH, and EPCAM. In conclusion, a sertoliform pattern can be part of the morphological spectrum of BRCA-related HGSC.

Diagnostic accuracy of HIK1083 and MUC6 as immunohistochemical markers of endocervical gastric-type adenocarcinoma: A systematic review and meta-analysis.

INTRODUCTION: HIK1083 and MUC6 have been used as immunohistochemical markers to differentiate gastric-type adenocarcinoma (GTAC) from other endocervical adenocarcinomas. We aimed to assess their diagnostic accuracy through a systematic review and meta-analysis. METHODS: Three electronic databases were searched from their inception to July 2022 for all studies assessing the expression in endocervical GTAC vs other endocervical adenocarcinomas. Diagnostic accuracy was assessed as sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), diagnostic odds ratio (DOR), and area under the curve (AUC) on SROC curves. RESULTS: Four studies with 343 patients were included. HIK1083 showed sensitivity= 0.64, specificity= 0.94, LR+ =8.30, LR-= 0.38, DOR= 33.36, AUC= 89.9%. MUC6 showed sensitivity= 0.51, specificity= 0.74, LR+ =1.96, LR-= 0.71, DOR= 3.48, AUC= 72.8%. CONCLUSION: HIK1083 showed high specificity and low sensitivity as a marker of GTAC, with moderate overall accuracy; MUC6 showed moderate specificity and low sensitivity, with low overall accuracy.

Characteristics of Placental Histopathology in Women with Uncomplicated Pregnancies Affected by SARS-CoV-2 Infection at the Time of Delivery: A Single-Center Experience.

The aim of this study was, firstly, to analyze the histopathological characteristics of placentas in women with uneventful pregnancies and affected by COVID-19 at the time of delivery; and secondly, to correlate histological findings to maternal and neonatal characteristics. In our single-center prospective observational study, 46 placentas from term uncomplicated singleton pregnancies of patients with a documented SARS-CoV-2 infection at the time of delivery underwent histological examination. Despite a normal feto-maternal outcome, most of the placentas (82.6%) presented signs of maternal vascular malperfusion, while features of fetal vascular malperfusion were found in 54% of cases. No correlation was detected between maternal and neonatal characteristics and the severity of blood circulation disease, and abnormal findings were also described in asymptomatic patients. Moreover, we did not find any maternal symptoms or clinical details allowing for the prediction of abnormal placental findings in pregnancy complicated by COVID-19 infection. Our results suggest that SARS-CoV-2 infection during pregnancy could lead to acute placental dysfunction.

Pilomatrix-like High-Grade Endometrioid Carcinoma of the Ovary: Case Report, Literature Review, and Differential Diagnosis.

Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) has recently been described as an aggressive variant of endometrial carcinoma. Herein, we described a case of ovarian PiMHEC, comparing it to endometrial PiMHEC and assessing previously published cases of putative ovarian PiMHEC. A 65-year-old woman underwent hysterectomy for an ovarian tumor characterized by solid nests of basaloid cells with prominent ghost cell keratinization. Immunohistochemistry showed nuclear ß-catenin and CDX2 expression and loss of estrogen and progesterone receptors and PAX8. These features were consistently observed in all previously published cases and may represent diagnostic criteria of PiMHEC. Other frequent features were geographic necrosis and a low-grade endometrioid component. CK7, neuroendocrine, and basal/squamous markers were inconsistently expressed. All cases with available follow-up showed poor prognosis. PiMHEC should be distinguished from mimickers, such as high-grade endometrioid carcinoma with geographic necrosis, low-grade endometrioid carcinoma with ghost cell keratinization, and undifferentiated/dedifferentiated carcinoma. In conclusion, PiMHEC can also occur in the ovary and shows several consistent clinical, morphological, and immunophenotypical features. These features support that PiMHEC is a distinct entity requiring an aggressive management.

Endometrial serous carcinoma with extensive squamous differentiation mimicking primary endometrial squamous cell carcinoma: Clinicopathological and molecular analysis of a case with literature review.

In the histological assessment of endometrial carcinoma, the presence of squamous differentiation is generally considered inconsistent with a serous histotype. Herein, we report a case of endometrial serous carcinoma with extensive squamous differentiation mimicking squamous cell carcinoma, with literature review. A 67-years-old-woman underwent hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node resection, omental and peritoneal biopsies, due to a 8 cm endometrial mass. Histologically, the tumor showed squamous carcinoma features with positivity for squamous cell markers (p40, p63, cytokeratin-5/6, cytokeratin-34ßE12) and negativity for Müllerian markers (PAX8, estrogen receptor, progesterone receptor). No immunohistochemical/molecular alterations typical of endometrioid carcinoma (i.e., PTEN loss, mismatch repair deficiency, nuclear ß-catenin expression, POLE mutation) were observed. P53 showed aberrant pattern and p16 showed basal positivity. The tumor infiltrated the myometrium full-thickness with extensive lymphovascular space invasion. Surprisingly, the sentinel lymph node metastasis showed overt serous carcinoma features. Additional sampling of the endometrial mass revealed a minor. In conclusion, serous carcinoma may show diffuse squamous differentiation. In the case of suspected primary endometrial squamous cell carcinoma, an extensive sampling is warranted.

Diagnostic accuracy of HNF1ß, Napsin A and P504S/Alpha-Methylacyl-CoA Racemase (AMACR) as markers of endometrial clear cell carcinoma.

Endometrial clear cell carcinoma (CCC) shows morphological overlap with endometrioid and serous carcinoma. We aimed to assess the accuracy of immunohistochemical diagnostic markers of CCC, i.e. HNF1ß, Napsin A and P504S/Alpha-Methylacyl-CoA Racemase (AMACR). A systematic review and meta-analysis was conducted by searching 4 electronic databases from their inception to April 2022 for all studies assessing HNF1ß, Napsin A and/or AMACR in endometrial CCC vs endometrioid/serous carcinomas. Diagnostic accuracy was assessed as sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratio (DOR) and area under the curve (AUC) on sROC curves. Eleven studies were included. HNF1ß positivity (any expression) showed sensitivity= 0.78; specificity= 0.81; LR+ =2.46; LR-= 0.38; DOR= 5.96; AUC= 0.79. Diffuse HNF1ß expression showed sensitivity= 0.53; specificity= 0.95; LR+ =9.68; LR-= 0.51; DOR= 18.02; AUC= 0.40. Napsin A positivity (any expression) showed sensitivity= 0.76; specificity= 0.97; LR+ =18.79; LR-= 0.27; DOR= 73.31; AUC= 0.81. Diffuse Napsin A expression showed sensitivity= 0.52; specificity= 0.99; LR+ =14.50; LR-= 0.55; DOR= 24.93; AUC= 0.98. AMACR positivity (any expression) showed sensitivity= 0.76; specificity= 0.86; LR+ =4.86; LR-= 0.30; DOR= 13.56; AUC was not assessable due to the presence of only 2 studies. In conclusion, HNF1ß, Napsin A and AMACR show moderate accuracy in identifying endometrial CCC. Considering only a diffuse expression of these markers as positive leads to high specificity but low sensitivity. In particular, Napsin A appears as the most specific marker of endometrial CCC.

P504S/alpha-methylacyl-CoA racemase, HNF1ß and napsin A in morular metaplasia and clear cell carcinoma of the endometrium: An immunohistochemical analysis.

AIMS: Endometrial morular metaplasia (MorM) can show cytoplasm clarification, which may mimic clear cell carcinoma (CCC), especially on biopsy. We aimed to assess the expression of CCC markers in MorM. METHODS: Twenty cases of MorM with areas of cytoplasmic clarification were assessed by immunohistochemistry for HNF1ß, Napsin A, and P504S/alpha-Methylacyl-CoA racemase (AMACR); 60 tumors were selected as controls (20 classical MorM, 20 conventional squamous differentiation and 20 CCC). RESULTS: Eighteen cases (90%) showed overt squamous/keratinizing areas within MorM, and 11 cases (55%) showed isolated ghost cells which might mimic the hyaline globules of CCC. All cases (100%) showed expression of AMACR, which was mostly diffuse and strong; in all cases, the expression was restricted to the prototypical MorM areas, while glandular areas and overtly squamous areas were negative. Twelve cases (60%) showed HNF1ß expression, which was focal/multifocal and/or weak; the expression was found in all tumor components. No case showed Napsin A expression in any component. Classical MorM showed similar immunophenotype, while conventional squamous differentiation did not show AMACR expression. Most CCC expressed AMACR (70%), HNF1ß (85%), and Napsin A (75%), mostly with diffuse and strong positivity. CONCLUSION: MorM may show features that mimic CCC and consistently expresses AMACR, which may be accompanied by HNF1ß expression; Napsin A is consistently negative instead. These findings should be considered to avoid overdiagnosis.

Mesenchymal Stem Cells from the Wharton's Jelly of the Human Umbilical Cord: Biological Properties and Therapeutic Potential.

Wharton's jelly mesenchymal stem cells (WJ-MSCs) are a class of stem cells with high differentiative potential, an immuno-privileged status and easy access for collection, which raise no legal or ethical issues. WJ-MSCs exhibit several features of embryonic stem cells, both in the phenotypic and genetic aspects, with only a few differences, such as a shorter doubling time and a more extensive ex vivo expansion capacity. WJ-MSCs have immunomodulatory properties, involving both innate and adaptive immune responses. This review focuses on the role of WJ-MSCs in the management of graft-versus-host disease (GvHD), a life-threatening complication of the allogenic transplantation of hematopoietic stem cells. Different studies documented the beneficial effect of the infusion of WJ-MSCs, even when not fully HLA identical, in patients with severe GvHD, refractory to standard treatment. Finally, we summarized current ongoing clinical trials with WJ-MSCs and their potential in regenerative medicine.