Gian Franco Zannoni

An update on the role of SMARCA4 deficiency in gynecological neoplasms: how and where

SMARCA4, encoding the BRG1 protein, is a crucial component of the SWI/SNF chromatin remodeling complex, essential for regulating gene expression and maintaining genomic integrity; our knowledge regarding the role of these genes continues to evolve. Deficiency or loss of SMARCA4 expression has been implicated in the development and progression of various gynecological neoplasms, notably small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), SMARCA4-deficient uterine sarcoma, and some subtypes of endometrial carcinoma such as undifferentiated or dedifferentiated carcinoma. Given its central role in oncogenesis, targeting SMARCA4-deficient tumors has become an area of active research, with potential therapeutic strategies above all in these aggressive gynecological tumor subtypes. This review summarizes current knowledge of the role of SMARCA4 deficiency in gynecological cancers, discussing the morphological and immunophenotypic characteristics of the different entities, emphasizing clinical implications and potential targeted therapies. Further understanding of its structure, function, and therapeutic vulnerabilities is crucial for improving patient outcomes.

HER2 in gynecological malignancies: Bridging the gap between standardized pathological assessment and precision therapy

Interobserver Agreement in Immunohistochemical Evaluation of Folate Receptor Alpha (FRα) in Ovarian Cancer: A Multicentre Study

Folate receptor alpha (FRα) is a high-affinity folate transporter overexpressed in various epithelial malignancies, particularly high-grade serous ovarian carcinoma. Given its restricted expression in normal tissues and accessibility in tumors, FRα is an emerging therapeutic target. Immunohistochemistry (IHC) is the standard method for FRα assessment; however, interpretation is semi-quantitative and prone to interobserver variability. This study aimed to evaluate interobserver agreement among 12 pathologists in the IHC assessment of FRα in ovarian cancer, focusing on internal control adequacy, staining intensity, and the percentage of FRα-positive tumor cells. Thirty-seven high-grade serous ovarian carcinoma cases were stained using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay. A reference panel of four expert pathologists established consensus diagnoses. Twelve pathologists independently assessed the slides, recording internal control adequacy, staining intensity (positive vs. negative), and percentage of FRα-positive tumor cells. Interobserver agreement was measured using Fleiss’ kappa and intraclass correlation coefficient (ICC). Agreement on internal control adequacy was almost perfect (κ = 0.84). Substantial agreement was observed for staining intensity (κ = 0.76), while percentage estimation showed almost perfect concordance (ICC = 0.89). Discrepancies were primarily confined to borderline cases (65–85% positivity) and tumors with intermediate staining, reflecting interpretive challenges near clinical decision thresholds. Pathologists demonstrated high reproducibility in FRα IHC assessment, particularly in estimating percentage positivity and control adequacy. These findings support the clinical utility of FRα IHC but underscore the need for standardized scoring criteria and potential integration of digital tools to enhance consistency, especially in borderline cases.

Folate Receptor Alpha in Advanced Epithelial Ovarian Cancer: Diagnostic Role and Therapeutic Implications of a Clinically Validated Biomarker

Folate receptor alpha (FRα), a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, plays a crucial role in folate transport during cell growth and development. While minimally expressed in most normal adult tissues, FRα is frequently overexpressed in several epithelial malignancies, particularly in high-grade serous ovarian carcinoma. An immunohistochemical (IHC) evaluation of FRα expression using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay is now approved as a companion diagnostic for selecting patients eligible for mirvetuximab soravtansine, an FRα-targeted antibody–drug conjugate. Clinical trials such as SORAYA and MIRASOL have demonstrated significant clinical benefit in platinum-resistant epithelial ovarian cancer patients with high FRα expression (≥75% of tumor cells with moderate to strong membrane staining). This review summarizes the biological significance of FRα in ovarian cancer progression, its predictive value for targeted therapy, and the technical aspects of IHC assessment, including scoring interpretation and pre-analytical variables. We also discuss heterogeneity in FRα expression across histological subtypes and tumor sites, as well as the impact of archival versus fresh tissue. Understanding FRα expression patterns across histologic subtypes and tissue samples is critical for optimizing clinical decision-making and expanding the role of FRα-targeted therapies in gynecologic oncology.

The multiple facets of ovarian high grade serous carcinoma: A review on morphological, immunohistochemical and molecular features

High-grade serous ovarian carcinoma (HGSOC) is the most aggressive subtype of epithelial ovarian cancer and a leading cause of mortality among gynecologic malignancies. This review aims to comprehensively analyze the morphological, immunohistochemical, and molecular features of HGSOC, highlighting its pathogenesis and identifying biomarkers with diagnostic, prognostic, and therapeutic significance. Special emphasis is placed on the role of tumor microenvironment (TME) and genomic instability in shaping the tumor's behavior and therapeutic vulnerabilities. Key advancements, such as the identification of TP53 and BRCA mutations, the classification of homologous recombination repair (HRR) deficiencies, and the clinical implications of biomarkers like folate receptor alpha (FRα) and PD-L1 are discussed. These findings reveal actionable insights into targeted therapies, including immune checkpoint inhibitors and PARP inhibitors, which hold promise for improving outcomes in HGSOC. This synthesis of knowledge aims to bridge gaps in understanding HGSOC's multifaceted biology, enhance clinical decision-making, and foster the development of precision therapies.

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

Abstract 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 β-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 β-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.

The first evidence of mismatch repair deficiency in mesonephric‐like adenocarcinoma of the endometrium: clinicopathological and molecular features of a case emphasising a possible endometrioid carcinogenesis

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Endometrial Cancer: A Review on Immunohistochemistry Staining Patterns and Clinical Implications

Among the four endometrial cancer (EC) TCGA molecular groups, the MSI/hypermutated group represents an important percentage of tumors (30%), including different histotypes, and generally confers an intermediate prognosis for affected women, also providing new immunotherapeutic strategies. Immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6 and PMS2) has become the optimal diagnostic MSI surrogate worldwide. This review aims to provide state-of-the-art knowledge on MMR deficiency/MSI in EC and to clarify the pathological assessment, interpretation pitfalls and reporting of MMR status.

Mesonephric-like adenocarcinoma of the endometrium: detailed molecular characterization of the first case showing a morphological continuum from mesonephric-like metaplasia and atypical mesonephric-like hyperplasia to adenocarcinoma

Mesonephric-like adenocarcinoma is a rare subtype of endometrial cancer, characterized by its histological and molecular overlap with mesonephric carcinoma of the uterine cervix. This study presents a unique case of mesonephric-like adenocarcinoma in the endometrium, accompanied by adjacent mesonephric-like hyperplasia and atypical mesonephric-like hyperplasia. Histologically, the transition from mesonephric metaplasia to adenocarcinoma was evident, and molecular analysis revealed shared mutations, including KRAS (p.G12D) in both atypical hyperplasia and adenocarcinoma, and a novel BCOR mutation (p.A1314Nfs*49) in the adenocarcinoma. These findings suggest a Müllerian origin of mesonephric-like adenocarcinoma via mesonephric transdifferentiation, challenging the traditional understanding of mesonephric histogenesis. The identification of these mutations underscores the potential for targeted therapies, particularly in cases with BCOR and KRAS mutations. This study is the first to document preneoplastic lesions in mesonephric-like adenocarcinoma, offering new insights into its pathogenesis and therapeutic implications.

The role of cytology in endometrial cancer: Diagnostic and clinical considerations from peritoneal/pelvic washings. Is it still a heated debate?

This editorial explores the diagnostic criteria and clinical implications of cytopathologic samples obtained from peritoneal/pelvic washings in patients with endometrial cancer.

Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer

The aim of this study is to analyze the prognostic role of lymph-vascular space invasion (LVSI), evaluated in a semi-quantitative fashion on prognosis of early stage, low risk endometrial cancer (EC). We enrolled patients who underwent surgery for endometrial cancer between 2003 and 2018 in two referral cancer center. All patients had endometrioid EC, G1-G2, with myometrial invasion <50%, and no lymph-node involvement. LVSI was analyzed in a semi-quantitative way, according to a 3-tiered scoring system in absent, focal and substantial. Among 524 patients, any positive LVSI was found in 57 patients (10.9%) with focal LVSI (n=35, 6.7%) and substantial LVSI (n=22, 4.2%). Substantial LVSI was associated to higher rate of G2 (p<0.001), myometrial infiltration (p=0.002) and greater tumor dimensions (p=0.014). Patients with substantial LVSI were more likely to receive adjuvant treatment (6.6% vs. 52.6%, p<0.001). The 5-year OS was 99.5% in patients with absent LVSI and 70.6% in those with substantial LVSI (p<0.001). The 5-year disease free survival (DFS) was 93.6% in patients with absent LVSI and 56.5% in those with substantial LVSI (p<0.001). The rate of distant failures increased from 1.8% for absent LVSI to 22.7% for substantial LVSI (p=0.002). In univariate analysis substantial LVSI was the strongest predictor of poor overall survival (hazard ratio [HR]=11.9, p=0.001). Multivariate analysis showed that substantial LVSI was an independent predictive factor of both recurrence (HR=5.88, p=0.001) and distant failure (HR=10.6, p=0.006). Substantial LVSI represents the strongest independent risk factor for decreased survival and distant relapse, indicating a role for potential hematogenous dissemination.

Evaluation of the one-step nucleic acid amplification method for rapid detection of lymph node metastases in endometrial cancer: prospective, multicenter, comparative study

To evaluate the diagnostic performance of the one-step nucleic acid amplification (OSNA) method for the detection of sentinel lymph node (SLN) metastases in women with apparent early-stage endometrial cancer compared with standard ultrastaging. Prospective, multicentric, interventional study. Patients with apparent early-stage endometrial cancer who underwent primary surgical staging with SLN mapping were included. SLNs were serially sectioned with 2 mm slices perpendicular to the longest axis of the node: the odd slices were submitted to ultrastaging, whereas the even slices were submitted to the OSNA analysis. Diagnostic performance was calculated taking ultrastaging as referral standard. Three-hundred and sixteen patients with 668 SLNs were included. OSNA assay detected 22 (3.3%) positive SLNs, of which 17 (2.5%) were micrometastases and 5 (0.7%) macrometastases, whereas ultrastaging detected 24 (3.6%) positive SLNs, of which 15 (2.2%) were micrometastases and 9 (1.3%) macrometastases (p=0.48). Regarding negative SLNs, OSNA detected 646 (96.7%) negative nodes, including 8 (1.2%) isolated tumor cells, while ultrastaging detected 644 (96.4%) negative nodes with 26 (3.9%) isolated tumor cells. Specificity of OSNA was 98.4% (95% CI 97.5 to 99.4), accuracy was 96.7% (95% CI 95.4 to 98.1), sensitivity was 50% (95% CI 30.0 to 70.0), while negative predictive value was 98.1% (95% CI 97.1 to 99.2). Discordant results were found in 22 SLNs (3.3%) corresponding to 20 patients (6.3%). These were 10 (1.5%) false-positive SLNs (all micrometastases): one (0.1%) of these was a benign epithelial inclusion at ultrastaging. There were 12 (1.8%) false-negative SLNs of OSNA, of which 9 (1.3%) were micrometastases and 3 (0.5%) macrometastases. Overall, 17/668 (2.5%) benign epithelial inclusions were detected at ultrastaging. The OSNA method had high specificity and high accuracy in detecting SLN metastasis in apparent early-stage endometrial cancer. The advantage of the OSNA method could be represented as the possibility to analyze the entire lymph node thus eliminating sampling bias.

Beyond the WHO 2020 Classification of Female Genital Tumors: Types of Endometrial Cancer: A Pathological and Molecular Focus on Challenging Rare Variants

Endometrial carcinoma is a heterogeneous group of malignancies characterized by distinct histopathological features and genetic underpinnings. The 2020 WHO classification has provided a comprehensive framework for the categorization of endometrial carcinoma. However, it has not fully addressed the spectrum of uncommon entities that are currently not recognized by the 2020 WHO and have only been described in the form of small case series and case reports. These neoplasms represent a real diagnostic challenge for pathologists; furthermore, their therapeutic management still remains controversial and information regarding tumor prognosis is very limited. This review aims to elucidate these lesser-known variants of endometrial carcinoma. We discuss the challenges of identifying these rare subtypes and the molecular alterations associated with them. Furthermore, we propose the need for expanded classification systems that include these variants to enhance clinical outcomes and research efforts. We believe that a better histological typing characterization of these entities may lead to more reproducible and accurate diagnoses and more personalized treatments. By raising awareness of these rare entities, we also hope to encourage further investigation and integration into clinical practice to improve patient care in endometrial carcinoma.

Morphological and immunohistochemical evaluation in distinguishing post-radiotherapy serous-like endometrial change (PoRSEC) and serous endometrial intraepithelial carcinoma (SEIC)

AbstractUteri from women undergoing chemoradiotherapy (CRT) may show reactive atypia which may mimic serous endometrial intraepithelial carcinoma (SEIC). We aimed to assess the prevalence and morphological/immunohistochemical features of post-radiotherapy serous-like endometrial changes (PoRSEC) in women undergone CRT for locally advanced cervical cancer, with a focus on the differential diagnosis with SEIC. Consecutive patients with locally advanced cervical cancer undergone CRT between 2011 and 2018 were reviewed. Endometrial histological specimens were assessed for the presence of PoRSEC. Twenty-two cases of SEIC were included for comparison. Immunohistochemistry for p53, p16, and Ki67 was performed. Out of 244 reviewed patients, 36 (14.7%) showed PoRSEC. The degree of nuclear atypia was similar between PoRSECs and SEIC. However, a papillary architecture with areas of confluent papillae was only observed in SEIC. SEIC cases showed a high mitotic activity as opposed to PoRSEC cases. The expression of p53 was aberrant in all SEICs but in none of the PoRSECs; however, 13/36 PoRSECs showed p53 positivity in most tumor cells, potentially mimicking a mutation pattern. A block-type p16 expression was observed in all SEICs and in 16/36 PoRSECs. Mean Ki67 expression was 26.9% in SEIC (range 5–70%) and 8.16% in PoRSEC (range 5–35%). While SEIC showed sharp morphological and immunohistochemical demarcation, PoRSEC were more heterogenous and merged imperceptibly with normal endometrium. In conclusion, PoRSEC may mimic SEIC both morphologically and immunohistochemically. However, a papillary architecture with cytological demarcation is typically observed in SEIC but not in PoRSEC.

Corded and hyalinized endometrioid endometrial carcinoma with high-grade features: a clinicopathological and TCGA-based molecular analysis

Corded and hyalinized endometrioid carcinoma (CHEC) typically shows low-grade features and "no specific molecular profile" (NSMP). This study aimed to perform a clinicopathological and molecular characterization of endometrial CHEC with high-grade features. Immunohistochemistry for cytokeratin AE1/AE3, e-cadherin, β-catenin, estrogen receptor, progesterone receptor, p53, p16, and mismatch repair proteins was performed. A next-generation sequencing kit was used to assess POLE, POLD1, APC, MLH1, MSH2, MSH6, PMS2, MUTYH, EPCAM, and CTNNB1. Molecular groups, i.e., POLE-mutant, mismatch repair deficient (MMRd), p53-abnormal, and NSMP, were assigned according to the TCGA classifier. Six high-grade endometrial CHECs were identified. The mean age was 57.5 years; 5/6 cases were uterine-confined. Five cases showed a diffusely and markedly atypical corded component and a MMRd or p53-abnormal signature; additional features included single-cell keratinization, necrosis, osteoid or myxoid/chondro-myxoid matrix, foci of anaplasia, and nuclear β-catenin expression. The remaining case showed a low mitotic count and a NSMP phenotype, with focal bizarre cells in an otherwise classical CH endometrioid carcinoma. All cases showed variably reduced expression of epithelial markers and hormone receptors in the corded component. No mutations were found in any of the analyzed genes. In conclusion, high-grade CHECs are a heterogeneous subset of biphasic endometrial carcinoma which show similarities and differences with classical CHEC and carcinosarcoma. These cases often show MMRd or p53-abnormal signatures.

TCGA Molecular Prognostic Groups of Endometrial Carcinoma: Current Knowledge and Future Perspectives

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage &gt;II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.

Endometrial carcinomas with dyshesive, eosinophilic, and vacuolated (histiocyte-like) tumor cells: a reactive-like phenotype associated with aggressive behavior

Herein, we present a clinicopathological and molecular analysis of four cases of endometrial carcinoma (EC) diffusely exhibiting dyshesive cells with wide eosinophilic and vacuolated cytoplasm (histiocyte-like tumor cells, HLTCs). We compared these HLTCs to similar cells found in microcystic, elongated and fragmented (MELF) pattern (n = 20) or after neoadjuvant chemotherapy (NAC) (n = 5). The four cases were endometrioid, serous, clear cell, and gastric-type; all were at FIGO stage ≥ III. HLTCs showed an epithelial Müllerian phenotype and at least focal CK20, HNF1β, and CK5/6 expression, with aberrant e-cadherin and β-catenin expression; two cases were MMR-deficient, and one was p53-abnormal; all were POLE wild type. MELF-associated and NAC-associated HLTCs showed similar morphological/immunophenotypical features. However, MELF-associated HLTCs were mainly intraglandular and inflammation-associated, did not form a distinct tumor component, and showed no relationship with lymph node metastases. In conclusion, different histotypes of EC may show a prominent HLTC component, which shows peculiar morphological/immunophenotypical features and appears associated with aggressive behavior.

Clear cell endometrial carcinoma precursors: presentation of two cases and diagnostic issues

Abstract Background The precursors of clear cell endometrial carcinoma (CC-EC) are still undefined. Here, we deal with the diagnostic issues related to CC-EC precursors by presenting a morphological, immunophenotypical and molecular study of two representative cases and discussing the relevant literature. Case presentation Our and previous cases suggest that clear cell endometrial intraepithelial carcinoma (CC-EIC) is a real entity, which may be distinguished from metaplastic/reactive changes and from its serous counterpart. CC-EIC appears associated with atrophic polyps and may be diagnosed based on morphological and immunophenotypical features of CC-EC in the absence of invasive disease. We described a p53-mutant putative precursor characterized by high-grade nuclei in the absence of other distinctive features. Two putative low-grade precursors resembled atypical tubal metaplasia and endometrial intraepithelial neoplasia, although immunohistochemistry could not support their relationship with CC-EC. Conclusions In conclusion, pathologists should be aware of the existence of CC-EIC, since its correct diagnosis may be crucial for a correct patient management. Although several putative earlier precursors have been described, they does not show univocal features that allow their recognition in the common practice. Further studies are necessary in this field.

Pathological features, immunoprofile and mismatch repair protein expression status in uterine endometrioid carcinoma: focus on MELF pattern of myoinvasion

Microcystic, elongated, and fragmented (MELF) pattern of myoinvasion has been related with increased risk of lympho-vascular space invasion (LVSI) and lymph node metastasis. We analysed a cohort of endometrioid endometrial carcinomas (EECs) to examine the relationships between the MELF pattern of invasion and the clinico-pathological and immunohistochemical features of EEC. 129 EECs were evaluated for the presence of MELF pattern and immunohistochemically tested for Mismatch repair (MMR) proteins, p16, p53 and beta-catenin. We observed 28 MELF + EECs and 101 MELF- EECs. LVSI was observed in 20 MELF + cases and in MELF- tumors. Lymph-node metastases were observed in 7 MELF + cases (2 macrometastases, 3 micrometastases and 2 ITCs). None of the MELF- cases showed micrometastases or ITCs, 18 cases had macrometastatic lymph-nodes. Statistical analysis showed that MELF + tumors carry an increased risk of developing nodal metastasis independent of tumor dimension and LVSI. Loss of MMR proteins expression was observed in 11 MELF + cases and 45 MELF- cases, respectively. Our data showed a higher frequency of immunohistochemical MLH1-PMS2 loss in MELF- pattern of invasion (32.67% of MELF- cases vs 21.43% of MELF + cases) but a higher prevalence of MSH2-MSH6 loss in MELF + pattern (7.14% in MELF + population vs 3.96% of MELF- population) CONCLUSIONS: The morphological recognition of MELF pattern is more reliable than immunohistochemical and molecular signatures of EEC in predicting the risk of nodal involvement. The observed higher prevalence of MSH2-MSH6 loss in MELF + group and MLH1-PMS2 loss in MELF- group may suggest a different molecular signature.

Atypical glandular cells and predictive features of malignancy in Pap smears: A retrospective monocentric study

Abstract Objective The introduction of cytological screening with the Papanicolau smear significantly reduced cervical cancer mortality. However, Pap smear examination can be challenging, being based on the observer ability to decode different cytological and architectural features. This study aims to evaluate the malignancy rate of AGC (atypical glandular cells) category, investigating the relationships between cytological and histological diagnosis. Methods Eighty‐nine patients, diagnosed as AGC at cytological evaluation and followed up with biopsy or surgical procedure at Policlinico Gemelli Hospital, Rome, Italy, were included in the study. The cytopathological architectural (feathering, rosette formation, overlapping, loss of polarity, papillary formation, three‐dimensional formation) and nuclear (N/C ratio, nuclear enlargement and hyperchromasia, mitoses, nuclei irregularity, evident nucleoli) features of AGC were evaluated. Statistical analyses were performed to assess cyto‐histological correlation and determine the relevance of architectural and nuclear features in the diagnosis of malignancy. Results Of the 89 AGC patients, 48 cases (53.93%) were diagnosed as AGC‐NOS and 41 (46.07%) were diagnosed as AGC‐FN, according to the Bethesda classification system. The follow‐up biopsies or surgical resections revealed malignancy in 46 patients (51.69%). The rates of malignancy for AGC‐NOS and AGC‐FN were 35.41% and 70.73% respectively. Furthermore, analysing cytopathological features, we found that both architectural and nuclear criteria were statistically significant ( p  &lt; 0.05). Only overlapping, nuclear irregularity and increased N/C ratio were not found to be statistically significant for detecting malignancy. Conclusions Cytological diagnosis of glandular lesions remains a valid tool, when appropriate clinical correlation and expert evaluation are available.

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 β-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.

Ganglioglioma arising in an ovarian teratoma

Aberrant non-canonical WNT pathway as key-driver of high-grade serous ovarian cancer development

Prognostic predictors in recurrent adult granulosa cell tumors of the ovary: a systematic review and meta-analysis

Ovarian adult granulosa cell tumours are low-grade malignant sex cord-stromal neoplasm with a low recurrence rate. Prognostic factors for recurrence include tumor stage, tumor rupture in Stage I neoplasms and the presence of residual tumors after surgery. However, in recurrent tumors, prognostic factors for overall survival (OS) are lacking. In the present paper, we conducted a systematic meta-analysis with the aim to assess prognostic factors for OS in patients with recurrent GCT. Electronic databases were searched for all studies assessing prognostic factors in recurrent adult granulosa cell tumor of the ovary. Student T test, Fisher's exact test and Kaplan-Meier survival analysis with long-rank test were used to assess differences among groups; a p value  II and extrapelvic anatomic sites of recurrences in patients with recurrent granuolase cell tumors of the ovary.

Neuroendocrine tumor (NET) of the vagina in the light of WHO 2020 2-tiered grading system: clinicopathological report of the first described case

Up to now, a vaginal well-differentiated neuroendocrine tumor (NET) has never been well described in the literature. A 2-cm vaginal nodule morphologically revealed a proliferation of mild to moderately atypical eosinophilic epithelioid cells, without tumor cell necrosis. Immunohistochemistry (IHC) showed positivity for CK (AE1/AE3), chromogranin A, and synaptophysin, focal positivity for CDX2, and negativity for PAX8 and TTF1. Metastatic origin was excluded by imaging and the morphological context with benign mucinous glands as present in the surgical resection specimen. Considering mitotic index and Mib1/Ki67 (8 mitoses/2 mm

European Society of Gynaecological Oncology Guidelines for the Management of Patients with Vulvar Cancer - Update 2023

As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) first published in 2017 evidence-based guidelines for the management of patients with vulvar cancer. To update the ESGO guidelines based on the new evidence addressing the management of vulvar cancer and to cover new topics in order to provide comprehensive guidelines on all relevant issues of diagnosis and treatment of vulvar cancer. The ESGO Council nominated an international development group comprised of practicing clinicians who provide care to vulvar cancer patients and have demonstrated leadership through their expertize in clinical care and research, national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (18 experts across Europe). To ensure that the statements were evidence-based, new data identified from a systematic search were reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 206 international practitioners in cancer care delivery and patient representatives. The updated guidelines cover comprehensively diagnosis and referral, staging, pathology, pre-operative investigations, surgical management (local treatment, groin treatment, sentinel lymph node procedure, reconstructive surgery), (chemo)radiotherapy, systemic treatment, treatment of recurrent disease (vulvar, inguinal, pelvic, and distant recurrences), and follow-up. Management algorithms are also defined.

Prognostic role of perineural invasion in vulvar squamous cell carcinoma: A systematic review and meta-analysis

The prognostic role of perineural invasion (PNI) in vulvar squamous cell carcinoma (VSCC) has not been fully established since few studies on this topic are currently available in the literature. In the present study, we conducted a systematic review and metanalysis of literature data in order to determine if PNI could be an independent prognostic predictor of patient's survival in VSCC. Four electronic databases (PubMed, ISI Web of Science, Scopus and Google Scholar) were searched from their inception to December 2021 for all studies assessing the prognostic value of PNI in VSCC. Multivariate hazard ratios (HRs) for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were pooled. Six studies with 1048 patients were included. PNI was significantly associated with decreased OS (HR = 2.687; p < 0.001), DSS (HR = 2.375; p = 0.014) and PFS (HR = 1.757; p = 0.001), with no statistical heterogeneity among studies and no significant risk of bias across studies. The present meta-analysis highlights that PNI is independently associated with unfavorable prognosis in patients with VSCC. Therefore, PNI should be included in the pathological report of VSCC and considered in combination with other risk factors as a possible criteria for prognostic assessment adjuvant treatment planning inclusion.

SATB2 is expressed in neuroendocrine carcinoma of the uterine cervix

Neuroendocrine carcinoma (NEC) of the uterine cervix is less characterized than neuroendocrine neoplasms of other sites such as of the digestive system and the lung. Special AT-rich sequence-binding protein 2 (SATB2) recently emerged as a marker of well-differentiated neuroendocrine tumors of the lower gastrointestinal (GI) tract. Among NECs, SATB2 is more frequently expressed in cutaneous Merkel cell carcinoma than in NEC of other anatomical sites. In our study, we performed an immunohistochemical study of SATB2 in 16 NECs of the uterine cervix, where the expression of these markers is still undefined. SATB2 was expressed in 12/16 cervical NECs (75%), with 7/16 cases (44%) showing SATB2 positivity in ≥ 50% of cells. In 7 cervical NECs associated with a non-neuroendocrine component, the expression of SATB2 was restricted to the neuroendocrine component. SATB2 was positive in all cases that expressed CDX2 (n = 7) and TTF1 (n = 5), with no evident association with p16 and p53. Our study demonstrated that SATB2 is often expressed in NECs of the uterine cervix. This information should be taken into account when assessing the origin of a NEC.

An exploratory assessment of early and delta PET radiomic features for outcome prediction in locally advanced cervical cancer

This study investigated whether radiomic features extracted from [ We retrospectively included LACC patients referred to our Institution from 2010 to 2016. [ 95 patients were included. With a median follow-up of 76.0 months (95% CI: 59.5-82.1), 31.6% of patients had recurrence/progression and 20.0% died of disease. None of the models could predict DFS (C-indices ≤ 0.72). Model performances for OS yielded slightly better results, with mean C-indices of 0.75 for both the radiomic and combined model based on early features, 0.79 and 0.78 for the radiomic and combined model derived from delta features, and 0.76 for the clinical models. [

In Vitro Study of [18F]F-FAPI-74 Feasibility in Vulvar Cancer

This study aims to investigate the expression of FAP by phosphor imaging in invasive vulvar squamous cell carcinoma specimens. This in vitro study will include all consecutive tumour specimens stored both in optimal cutting temperature (OCT) compound and formalin-fixed paraffin-embedded (FFPE) from patients with a first diagnosis of vulvar squamous cell carcinoma who underwent surgery at Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.