The emerging and challenging role of PD-L1 in patients with gynecological cancers: An updating review with clinico-pathological considerations.

Over recent years, there has been significant progress in the development of immunotherapeutic molecules designed to block the PD-1/PD-L1 axis. These molecules have demonstrated their ability to enhance the immune response by prompting T cells to identify and suppress neoplastic cells. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in gynecological malignancies is extremely variable based on tumor stage and molecular subtypes. As a result, a class of monoclonal antibodies targeting the PD-1 receptor and PD-L1, known as immune checkpoint inhibitors, has found successful application in clinical settings. In clinical practice, the standard method for identifying suitable candidates for immune checkpoint inhibitor therapy involves immunohistochemical assessment of PD-L1 expression in neoplastic tissues. The most commonly used PD-L1 assays in clinical trials are SP142, 28-8, 22C3, and SP263, each of which has been rigorously validated on specific platforms. Gynecologic cancers encompass a wide spectrum of malignancies originating from the ovaries, uterus, cervix, and vulva. These neoplasms have shown variable response to immunotherapy which appears to be influenced by genetic and protein expression profiles, including factors such as mismatch repair status, tumor mutational burden, and checkpoint ligand expression. In the present paper, an extensive review of PD-L1 expression in various gynecologic cancer types is discussed, providing a guide for their pathological assessment and reporting.

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

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 < 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.

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.

Gastric (gastrointestinal)-type endometrial adenocarcinoma presenting as a solitary endometrial polyp: a case report and literature review on a novel and potentially aggressive endometrial cancer histotype.

Gastric-type carcinoma of the endometrium is a rare endometrial cancer histotype, recently introduced in the 2020 WHO classification of the female genital tract tumors. Clinico-pathological features, as well as treatment strategies for this rare histotype, are not fully defined. We herein present an unusual case of endometrial carcinoma with mucinous features arising in a 58-year-old menopausal woman. Morphological features of the present case as well as immunohistochemical profile were consistent with gastrointestinal differentiation. Therefore, after clinical and imaging studies ruled out the possibility of a metastatic origin, a final diagnosis of gastric-type carcinoma of the endometrium was rendered.

Postchemotherapy Endometrioid to Gastrointestinal Histotype Shift in Recurrent Endometrial Carcinoma.

Herein, we report a case of low-grade endometrial endometrioid carcinoma recurred on the vaginal stump, which showed a complete histotype shift toward a gastrointestinal-type carcinoma after chemotherapy. The recurrent tumor increased in volume during chemotherapy. Postchemotherapy histologic examination showed a pure mucinous signet-ring cell pattern with positivity for cytokeratin 20 and CDX2, focal SATB2 expression and negativity for cytokeratin 7 and estrogen and progesterone receptors. Such features led to consider a diagnosis of metastasis from a primary carcinoma of the gastrointestinal tract. The accurate exclusion of any primary lesions of gastrointestinal and of other sites allowed identifying the tumor as the recurrent endometrial carcinoma. Our case highlights that chemotherapy may induce a histotype shift from endometrioid carcinoma to gastrointestinal-type carcinoma; such occurrence might be a mechanism of resistance and might provide new insights on the sensitiveness of different histotypes to systemic therapies. Considering the possibility of a shift from endometrioid to gastrointestinal-type carcinoma may be useful for a correct diagnosis and an appropriate patient management.

Retrospective study of histopathological and prognostic characteristics of primary fallopian tube carcinomas: twenty-year experience (SOCRATE).

OBJECTIVE: Primary fallopian tube carcinoma represents a rare entity, accounting for about 0.75%-1.2% of all gynecological malignancies. The rationale of our study is to describe the prognosis of primary fallopian tube carcinoma. METHODS: We retrospectively identified patients with FIGO stage I-IV, all histology types and grading primary fallopian tube carcinoma treated in three major oncological centers between January 2000 and March 2020. Exclusion criteria were bulky tubo-ovarian carcinomas, isolated serous tubal intraepithelial carcinoma or neoadjuvant chemotherapy. RESULTS: A total of 61 patients were included. The vast majority of primary fallopian tube carcinomas were serous (96.7%) and poorly differentiated (96.7%) and arose from the fimbriated end of the tube (88.5%). Larger tumor size correlated with higher probability of correct preoperative differential diagnosis of primary fallopian tube carcinoma (p=0.003). Up to 82.4% of patients with small tumors (≤15 mm) presented with high FIGO stage (≥IIA). The most common site of metastasis was pelvic peritoneum (18.8%) and among 59% of patients who underwent lymphadenectomy smaller tumors had higher rate of nodal metastasis (42.9%≤10 mm vs 27.3%>50 mm). After 46.0 months of mean follow-up there were 27 recurrences (48.2%). The most common site of relapse was diffuse peritoneal spread (18.5%). The 5-year disease-free survival was 45.2% and 5-year overall survival was 75.5%. Of note, 42.9% of patients with stage IVB survived >36 months. CONCLUSION: Primary fallopian tube carcinoma is a biologically distinct tumor from primary epithelial ovarian carcinoma and it is mostly located in the fimbriated end of the tube. In addition, it is characterized by a high rate of retroperitoneal dissemination even at apparently an early stage and its size does not correlate with FIGO stage at presentation.

Diagnostic impact of safety protocols for processing peritoneal washing specimens during the global pandemic of coronavirus disease 2019: A comparative study from 195 cytological samples.

BACKGROUND: The global pandemic of the coronavirus disease 2019 represents a major concern for health services worldwide, and has also induced major changes in cytopathology practice. AIM: We aimed to verify the diagnostic performance of cytological evaluation under a new safety protocol during the pandemic compared to the standard pre-pandemic procedure. We also aimed to assess how cytological diagnoses and sampling were impacted during the pandemic period compared to the pandemic-free period in 2019. MATERIALS AND METHODS: Cytological samples of peritoneal washings taken during the first 10 months of the pandemic emergency in Italy (March 11, 2020 to January 11, 2021) were compared to samples from the preceding 10-month time frame (May 11, 2019 to March 10, 2020). RESULTS: One hundred ninety-five specimens were analysed in the present study. We observed no noticeable differences in cytological diagnoses during the pandemic period compared to the pre-pandemic period. The case numbers by diagnostic category for the pre-pandemic vs pandemic periods, respectively, were as follows: non-diagnostic, 0 vs 0 cases; negative for malignancy, 86 vs 52 cases; atypia of uncertain significance, 7 vs 1 cases; suspicious for malignancy, 0 vs 2 cases; malignant, 42 vs 4 cases. CONCLUSION: While a consistent reduction in the number of cytological examinations has been observed during the COVID-19 period, our institutional safety protocol for processing cytological samples did not affect the diagnostic reliability of peritoneal washing cytology.

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

BACKGROUND: 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. METHODS: 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 < 0.05 was considered significant. RESULTS: Eleven studies analyzing 102 recurrent tumors were included in the systematic review. Tumor stage and localization of recurrent tumors were significantly associated with OS on Kaplan-Meier analysis; Cox regression analysis showed a HR of 0.879 for the stage II, of 3.052 for the stage III, and of 2.734 for stage IV tumor was significantly associated with OS (p = 0.037); observed HRs for abdominal and thoracic locations were of 2.405 and of 4.024, respectively. CONCLUSIONS: In conclusion, the present article emphasizes the prognostic significance of tumor stage > II and extrapelvic anatomic sites of recurrences in patients with recurrent granuolase cell tumors of the ovary.

Biomarker characterization in endometrial cancer in Italy: first survey data analysis.

Objective: Endometrial carcinoma (EC) is the most common gynecological malignant disease in high income countries. The 2020 edition of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract underlines the important clinical implications of the new integrated histo-molecular classification system, in order to correctly define the specific prognostic risk group. This survey analysis will focus on the most commonly adopted immunohistochemical and molecular biomarkers used in daily clinical characterization of a diagnosed endometrial carcinoma in Italian labs. Methods: An evaluation questionnaire was distributed to 41 Italian pathology laboratories. Normal habits in EC evaluation, especially regarding mismatch repair status (MMR) and microsatellite instability (MSI), were collected. A summary and a descriptive statistical analysis were used to show the current practice of each laboratory. Results: The analysis of MMR status by immunohistochemistry (IHC) is carried out on the majority of all EC samples. The most frequent strategy for the analysis of MMR status in EC is IHC of four proteins (PMS2, MSH6, MSH2, MLH1). MSI analysis by molecular method in endometrial cancer is rarer and more restricted to some circumstances. Hypermethylation of the MLH1 promoter by methylation-specific PCR and pyrosequencing was analyzed in case of negative expression of MLH1/PMS2. Also, the analysis of p53 in EC is performed in the majority of cases. POLE mutational profiling is adopted only in a limited number of laboratories. Fifty-five percent of Italian laboratories refer to national/international guidelines when analyzing biomarkers in EC (among those, 45% use the ESGO Guidelines, 18% ASCO-CAP, 18% AIOM, 14% WHO, 5% British Association of Gynaecological Pathologist, 5% ESMO, 5% NCCN). Conclusions: Adoption of guidelines and standardization of pre-analytical and analytical procedures are effective tools for adequate EC prognostic risk stratification and high quality standard of care.

Clinico-pathological significance of TCGA classification and SWI/SNF proteins expression in undifferentiated/dedifferentiated endometrial carcinoma: A possible prognostic risk stratification.

BACKGROUND: Undifferentiated/dedifferentiated endometrial carcinoma (UEC/DDEC) is a heterogeneous entity, which may show any of the TCGA molecular signatures and loss of the switch/sucrose nonfermentable (SWI/SNF) proteins expression. AIM: To assess the clinico-pathological significance of the TCGA molecular groups and SWI/SNF proteins expression in UEC/DDEC, through a quantitative systematic review. METHODS: Electronic databases were searched for all studies assessing the TCGA molecular groups, i.e. POLE-mutant, mismatch repair-deficient (MMRd), p53-abnormal (p53abn) and no specific molecular profile (NSMP), and/or the SWI/SNF proteins (SMARCA4/BRG1, SMARCB1/INI1, ARID1B) expression in UEC/DDEC. 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<0.05 was considered significant. RESULTS: Eight studies were included in the systematic review. Among the TCGA groups, the mean patient age was significantly higher in the p53abn group than in the NSMP group (p = 0.048). The POLE-mutant group showed advanced FIGO stage (III-IV) significantly less commonly than the NSMP (p = 0.003) and MMRd (p = 0.008) groups, and a significantly better prognosis than the NSMP (p = 0.007), MMRd (p = 0.011) and p53abn (p = 0.045) groups.The SWI/SNF-deficient cases showed a significantly worse prognosis than the SWI/SNF-intact cases (p = 0.010), while no significant differences were found regarding patient age and FIGO stage. CONCLUSIONS: Among UEC/DDEC, POLE-mutant cases show good prognosis, while SWI/SNF-deficient cases show poor prognosis. The other TCGA molecular subtypes seem to be characterized by an intermediate biological behaviour. On this account, UEC/DDEC patients might be subdivided into three risk groups based on POLE and SWI/SNF status. Further studies are necessary in this field.

Clear cell endometrial carcinomas with mismatch repair deficiency have a favorable prognosis: A systematic review and meta-analysis.

INTRODUCTION: In the ESGO/ESTRO/ESP guidelines for endometrial carcinoma management, the risk category of clear cell carcinoma (CCC) is not well defined. In fact, while p53-abnormal (p53abn) CCC are known to be aggressive, the prognosis of mismatch repair-deficient (MMRd) and p53-wild-type (p53wt) CCCs is less clear. OBJECTIVE: To assess the prognostic value of the MMRd and p53wt groups in CCC through a systematic review and meta-analysis. METHODS: Electronic databases were searched from their inception to February 2021. All studies reporting p53 expression, MMR proteins expression and survival outcomes in endometrial CCC (either pure or mixed) were included. Kaplan-Meier and Cox regression survival analyses with hazard ratio (HR) for overall survival (OS) were performed by using the p53abn group as reference; a significant p-value<0.05 was adopted. RESULTS: Six studies with 136 CCC (114 pure and 22 mixed) were included. Five-year OS was 95.7 ± 4.3% in the MMRd group, 48.4 ± 8.4% months in the p53wt group and 40.6 ± 10.4% in the p53abn group. The hazard of death was significantly lower in the MMRd group than in the p53abn group (HR = 0.062; p = 0.007), while it did not significantly differ between the p53wt and the p53abn group (HR = 0.673; p = 0.222). The POLEmut group could not be analyzed due to the absence of deaths. Similar results were observed in the pure CCC and mixed CCC subgroups. CONCLUSION: MMRd CCCs seem to have a favorable prognosis and might be lumped together with MMRd endometrioid carcinoma for management purpose. On the other hand, p53wt CCCs appear prognostically more similar to p53abn CCCs.

PET/CT-Detected myofibroblastoma of the breast with bizarre cells: A potential diagnostic pitfall of malignancy.

Myofibroblastoma (MFB) is a rare benign mesenchymal tumor usually occurring in the breast parenchyma. This tumor can present as a palpable nodule or can be incidentally detected as a nonpalpable mass on routine screening mammogram. We first report a rare case of histologically proven MFB of the breast revealed by fluoro-deoxyglucose uptake on PET-CT examination in a patient with a lung nodule. Tumor exhibited an unusual morphology, being predominantly composed of polygonal, epithelioid, and deciduoid-like cells set in a myxoid stroma. The most striking feature was the multifocal presence of atypical/bizarre, mono/bi-nucleated cells that, in addition to diffuse myxoid stromal changes, were a concern of malignancy, especially on core biopsy. The final diagnosis of MFB was achieved on surgically resected specimen and, similarly to other benign soft tissue tumors (especially leiomyoma and schwannoma/neurofibroma), the term "bizarre cell MFB of the breast" is proposed to emphasize the degenerative/reactive nature of the atypia.

The Role of Genital Tract Microbiome in Fertility: A Systematic Review.

The human microbiome plays a crucial role in determining the health status of every human being, and the microbiome of the genital tract can affect the fertility potential before and during assisted reproductive treatments (ARTs). This review aims to identify and appraise studies investigating the correlation of genital microbiome to infertility. Publications up to February 2021 were identified by searching the electronic databases PubMed/MEDLINE, Scopus and Embase and bibliographies. Only full-text original research articles written in English were considered eligible for analysis, whereas reviews, editorials, opinions or letters, case studies, conference papers, and abstracts were excluded. Twenty-six articles were identified. The oldest studies adopted the exclusive culture-based technique, while in recent years PCR and RNA sequencing based on 16S rRNA were the most used technique. Regardless of the anatomical site under investigation, the Lactobacillus-dominated flora seems to play a pivotal role in determining fertility, and in particular Lactobacillus crispatus showed a central role. Nonetheless, the presence of pathogens in the genital tract, such as Chlamydia trachomatis, Gardnerella vaginalis, Ureaplasma species, and Gram-negative stains microorganism, affected fertility also in case of asymptomatic bacterial vaginosis (BV). We failed to identify descriptive or comparative studies regarding tubal microbiome. The microbiome of the genital tract plays a pivotal role in fertility, also in case of ARTs. The standardization of the sampling methods and investigations approaches is warranted to stratify the fertility potential and its subsequent treatment. Prospective tubal microbiome studies are warranted.

Cerebellar Metastasis From Ovarian Carcinoma Harboring PIK3CA-Activating Mutation: A "Clear" Explanation for Unexpected "Vertigo".

Brain metastasis is a rare and generally late manifestation of an advanced-stage, high-grade serous ovarian carcinoma. Nowadays, the improved control of intra-abdominal disease by surgery and platinum-based chemotherapy results in a longer survival, allowing distant metastasis to implant and grow in the brain parenchyma. Herein, we describe a unique case of a cerebellar metastasis from clear cell ovarian carcinoma that initially presented as a FIGO Stage IC cancer. Surprisingly, 6 mo after surgery, the patient was in good condition with complete disappearance of symptoms and no evidence of recurrence. This relatively good biologic behavior may be explained by the presence of a PIK3CA-activating mutation in exon 9 which as previously reported in the literature, may be associated with better prognosis. To the best of our knowledge, this is the first reported case of cerebellar metastasis from ovarian clear cell carcinoma. In the presence of neurological symptoms, both clinicians and pathologists must be aware of this rare possibility, to assure correct patient management and effective therapeutic options. Generally, the prognosis of epithelial ovarian cancer patients with brain metastases is poor. PIK3CA mutations could be a good prognostic indicator in clear cell carcinomas.

Standard ultrastaging compared to one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node metastases in early stage cervical cancer.

OBJECTIVE: We compared ultrastaging and one-step nucleic acid amplification (OSNA) examination of sentinel lymph nodes in two homogeneous patient populations diagnosed with early stage cervical cancer. The primary aim of our study was to evaluate the rate and type of sentinel lymph node metastases detected by ultrastaging and OSNA assay. Secondary aims were to define the sensitivity and the negative predictive value of sentinel lymph node biopsy assessed with OSNA and ultrastaging and to define the role of sentinel lymph node assessment in predicting non-sentinel lymph node status. METHODS: Consecutive patients who underwent surgery (radical hysterectomy or trachelectomy or cervical conization) at our institution, between January 2018 and March 2020, were enrolled. All patients had a preoperative diagnosis of early-stage cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) 2018 stages IA-IIB) and underwent sentinel lymph node assessment with ultrastaging or OSNA. Patients with advanced FIGO stages and special histology subtypes (other than squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) or patients with sentinel lymph nodes analyzed only with hematoxylin and eosin were excluded. Clinical data were compared using the χ2 test and Fisher's exact test. A κ coefficient was determined with respect to lymph node assessment. A p value <0.05 was considered statistically significant. RESULTS: A total of 116 patients were included in this retrospective analysis (53 ultrastaging, 63 OSNA). Overall, 531 and 605 lymph nodes were removed in the ultrastaging and OSNA groups, respectively, and 140 and 129 sentinel lymph nodes were analyzed in the ultrastaging and OSNA groups, respectively. 22 patients had metastatic sentinel lymph nodes: 6 (11.3%) of 53 patients in the ultrastaging group and 16 (25.4%) of 63 patients in the OSNA group. The total amount of positive SLNs was 7 (5%) of 140 in the ultrastaging group and 21 (16.3%) of 129 in the OSNA group, respectively (p=0.0047). Pelvic lymphadenectomy was performed in 26 (49.1%) of 53 patients in the ultrastaging group and in 34 (54%) of 63 patients in the OSNA group due to comorbidities. Metastatic non-sentinel lymph nodes were found in 4 patients: 2 (7.7%) of 26 patients in the ultrastaging group and 2 (5.9%) of 34 patients in the OSNA group, respectively. The total amount of positive pelvic lymph nodes was 3 (0.6%) of 531 in the ultrastaging group and 4 (0.7%) of 605 in the OSNA group (p=0.61). In the OSNA group, only 2 patients with negative sentinel lymph nodes had metastatic disease in the pelvic lymph nodes. By contrast, no patients with OSNA-positive sentinel lymph nodes had metastases in the pelvic lymph nodes. In the ultrastaging group, all patients with negative sentinel lymph nodes did not have metastatic disease in other pelvic lymph nodes. CONCLUSIONS: OSNA assessment of sentinel lymph nodes was associated with a negative predictive value of 91% but poor reliability in detecting node metastases in non-sentinel pelvic lymph nodes. Of note, the ultrastaging protocol revealed higher sensitivity and more reliability in predicting pelvic non-sentinel lymph node status.

The Many Faces of Endometriosis-Related Neoplasms in the Same Patient: A Brief Report.

INTRODUCTION: Endometriosis is a common benign gynecological condition that can be associated with a slightly increased risk of developing a wide range of malignancies. CASE PRESENTATION: We herein report a singular case of a 62-year-old woman with a history of pelvic endometriosis, referred to our institution for chronic pelvic pain and uterine bleeding, with clinical and radiological evidence of left ovarian mass of 18 cm in largest diameter and multiple nodular mural lesions of the uterine cavity. The patient underwent exploratory laparotomy followed by hysterectomy, bilateral salpingo-oophorectomy, and omentectomy with pelvic lymph-node sampling. The histological examination of the ovarian mass revealed a clear-cell ovarian carcinoma arising from an endometriotic cyst. The microscopic examination of the uterine cavity showed multiple conventional leiomyomas, diffuse foci of adenomyosis, and a 1.5-cm yellow nodule diagnosed as low-grade endometrial stromal sarcoma associated with glandular atypical differentiation and with extension into parametrial and omental tissues. Following the diagnosis, the patient was treated with chemotherapy, radiation therapy, and hormonal therapy and after 9 months of follow-up is alive without local recurrences and distant metastases. DISCUSSION/CONCLUSIONS: To the best of our knowledge, the present case represents the first evidence of the simultaneous occurrence of clear-cell carcinoma and low-grade endometrial stromal sarcoma arising within ovarian and uterine endometriotic foci, respectively.

Biosafety procedures for handling intraoperative surgical samples during COVID-19 pandemic: an Italian pathology laboratory experience.

Up to now, Italy is one of the European centers with the most active Coronavirus cases with 233,836 positive cases and 33,601 total deaths as of June 3rd. During this pandemic and dramatic emergency, Italian hospitals had also to face neoplastic pathologies, that still afflict the Italian population, requiring urgent surgical and oncological treatment. In our Cancer Center Hospital, the high volume of surgical procedures have demanded an equally high volume of intraoperative pathological examinations, but also posed an additional major challenge for the safety of the staff involved. The current commentary reports our experience in the past two months (since March 9th) for a total of 1271 frozen exams from 893 suspect COVID-19 patients (31 confirmed).

Fibulin-3 immunoexpression in malignant mesothelioma due to fluoro-edenite: a preliminary report.

An increased standardized incidence and mortality rate were reported due to malignant mesothelioma (MM) in Biancavilla. Environmental investigations showed the presence of an asbestiform fiber: fluoro-edenite (FE). MM develops with a latency of 20-60 years from exposure and specific and sensitive biomarkers are urgently needed. For this purpose, we evaluated Fibulin-3 (Fb-3) immunoexpression in human cases of MM related to FE exposure and its prognostic role. Immunohistochemical analysis of Fb-3 was carried out in eight MM patients resident in Biancavilla and the analysis showed evidence of environmental exposure to FE fibers. Six MM cases (3 epithelioid and 3 biphasic) showed a high immunoexpression of Fb-3 in neoplastic cells with nuclear and cytoplasmic localization. One epithelioid and one biphasic subtype did not show Fb-3 immunostaining. The results demonstrate the implication of Fb-3 in MM due to FE exposure and may possibly suggest its potential role as a diagnostic and prognostic marker.

Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation.

Autophagy represents a catabolic process in which cellular protein and organelles are engulfed into autophagosomes, digested in lysosomes and reutilized for the cellular metabolism. In neoplastic conditions, autophagy may act either as a tumour suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumour growth. Although enhanced autophagy has been reported in hypoxic areas of solid tumors, there are only few ultrastructural reports concerning the relationships between autophagy and tumor grade. In the present study, we have performed an ultrastructural investigation aimed to document autophagy in a cohort of advanced gastric carcinomas of tubular type, correlating the observed findings with low and high tumor grade. Among 71 surgically resected cases of advanced gastric carcinomas, we have selected twelve low-grade and thirteen high-grade tubular adenocarcinomas. Autophagic vacuoles (AV) were only occasionally found in low-grade tubular carcinomas, while they constituted a frequent finding in high-grade ones (p < 0.01). Moreover, in high-grade tubular adenocarcinomas, our data revealed a morphologic association between autophagy and nuclear changes, such as multinucleation, micronucleation and nuclear buds, largely considered as ultrastructural aspects of mitotic instability. However, an increased autophagy was associated with organelle-poor cytoplasm or a senescent phenotype, characterized by lipofuscin granules and cytoplasmic vacuoles. In the light of our observations, it may be suggested that autophagy should be considered a phenomenon mainly related to the cellular differentiation and tumor progression.