Endometriosis-Related Ovarian Cancer: Where Are We Now? A Narrative Review towards a Pragmatic Approach.

BACKGROUND: Endometriosis affects more than 10% of reproductive-aged women, causing pelvic pain and infertility. Despite the benign nature of endometriosis, ovarian endometriomas carry a higher risk of developing endometrioid carcinomas (EnOCs) and clear cell ovarian carcinomas (CCCs). Atypical endometriosis, defined as cytological atypia resembling intraepithelial cancer, is considered the precursor of endometriosis-associated ovarian cancer (EAOC). This narrative review aims to provide an overview of EAOC, proposing a practical approach to clinical and therapeutic decision making. METHODS: An electronic literature search was conducted from inception up to January 2023, using the MEDLINE database via PubMed to evaluate the existing literature on EAOC, including its pathogenesis, the diagnostic process, and the therapeutic possibilities, with articles not relevant to the topic or lacking scientific merit being excluded. RESULTS: Eighty-one articles were included in the review to present the current state of the art regarding EAOC. A pragmatic clinical flowchart is proposed to guide therapeutic decisions and improve patient outcomes. CONCLUSIONS: Endometriosis patients may have an increased risk of developing EAOC (either EnOC or CCC). Despite not being fully accepted, the concept of AE may reshape the endometriosis-ovarian cancer relationship. Further research is needed to understand the unaddressed issues.

Extrauterine adenomyoma: A case report and systematic review of the literature.

OBJECTIVE: To describe a case of extrauterine adenomyoma (EA) and review all the cases of EA in the literature. METHODS: Pubmed/MEDLINE, Embase, and Google Scholar from 1807 to December 2022. All studies reporting the histologic diagnosis of an EA. We collected the following data: patient's age, size and location of adenomyoma, presence of endometriosis and adenomyosis, past gynecologic treatment, symptoms, diagnostic imaging, surgical intervention, alternative/adjuvant treatment, associated malignancy, and follow up. RESULTS: Sixty-seven studies with 85 patients were included. Pain was the most frequent symptom (69.5%). Among diagnostic examinations, ultrasonography was used in 60 out of 81 reported cases, with several radiologic features described. EA was located inside the pelvis in 77.6% of patients. Adnexa were the most frequent site of the disease (24, 28.2%). History of endometriosis or adenomyosis was described in 35 patients (35, 41.2%). Uterine tissue morcellation was reported in 6 of the 85 patients (7.1%). Associated malignancy was detected in 9 out of 85 patients with available data (10.6%). There were two recurrences of disease. CONCLUSION: Specific imaging features of EA are yet to be described in the literature. History of endometriosis and adenomyosis or uterine tissue morcellation may be suggestive of EA. Histologic examination can give a definitive diagnosis and exclude malignant transformation.

High Incidence of Thyroid Cancer in Southern Tuscany (Grosseto Province, Italy): Potential Role of Environmental Heavy Metal Pollution.

The incidence of thyroid cancer (TC) in Italy is one of the highest in Europe, and the reason for this is unclear. The intra-country heterogeneity of TC incidence suggests the possibility of an overdiagnosis phenomenon, although environmental factors cannot be excluded. The aim of our study is to evaluate the TC incidence trend in southern Tuscany, Italy, an area with particular geological characteristics, where the pollution and subsequent deterioration of various environmental matrices with potentially toxic elements (heavy metals) introduced from either geological or anthropogenic (human activities) sources are documented. The Tuscany cancer registry (ISPRO) provided us with the number of cases and EU standardized incidence rates (IR) of TC patients for all three provinces of southeast Tuscany (Siena, Grosseto, Arezzo) during the period of 2013-2016. In addition, we examined the histological records of 226 TC patients. We observed that the TC incidence rates for both sexes observed in Grosseto Province were significantly higher than those observed in the other two provinces. The increase was mostly due to the papillary (PTC) histotype (92% of cases), which presented aggressive variants in 37% of PTCs and tumor diameters more than 1 cm in 71.3% of cases. We demonstrated a high incidence of TC in Grosseto province, especially among male patients, that could be influenced by the presence of environmental heavy metal pollution.

Routine IgG4 staining in minor salivary gland biopsy in a cohort of Italian Caucasian patients suffering from xerostomia.

Objectives: IgG4-related disease is a potentially systemic disease mimicking and overlapping with different autoimmune diseases, such as primary Sjögren's syndrome (pSS). The involvement of salivary glands, previously called Mikulicz's disease, has been reclassified as IgG4-related sialadenitis (SA). The aim of this study was to assess the prevalence of IgG4-SA in a cohort of Italian Caucasian patients presenting with xerostomia and to evaluate the eventual overlap between IgG4-SA and pSS. Material and methods: We included 154 patients - 15 males and 139 females, mean age 54.18 ±14.24 years, who underwent minor salivary gland biopsy between March and December 2019 for xerostomia. Histopathology was evaluated using Chisholm-Mason (CM) and focus score (FS) for pSS and immunohistochemical study with IgG4 staining for IgG4-SA were performed. Serum autoantibodies (anti-SSa/RoAb, anti-SSB/LaAb, antinuclear antibodies, rheumatoid factor) were also assessed. Results: In 69 patients (44.8%) FS 0 was found, while FS ≥ 1 was presented in 85 (55.2%). Chisholm-Mason score < 3 and CM ≥ 3 was found in 73 (47.4%) and 81 (52.6%) cases, respectively. IgG4/high-power field level was 20 in 3 pSS patients (1.9%), but none of them had an IgG4/IgG ratio ≥ 40, as well as tissue fibrosis with storiform pattern, obliterative vasculitis, and tissue eosinophilia. The diagnosis of pSS, was confirmed in 92 patients (59.74%). No patient was definitively diagnosed with an IgG4-related disease. Conclusions: In the case of xerostomia, the evaluation of the histopathological specimen for IgG4 should not be routinely performed, at least in an Italian-based Caucasian population. Moreover, immunohistochemistry should not be requested in the case of a negative result of biopsy for pSS.

Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression.

AIMS: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. METHODS AND RESULTS: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. CONCLUSIONS: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.

Corrigendum: Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes.

[This corrects the article DOI: 10.3389/fonc.2021.649435.].

Epstein-Barr virus reactivation influences clonal evolution in human herpesvirus-8-related lymphoproliferative disorders.

BACKGROUND: Human herpesvirus-8 (HHV8) is a lymphotropic virus associated with different lymphoproliferative disorders, including primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), diffuse large B-cell lymphomas, not otherwise specified, and the rare entity known as germinotropic lymphoproliferative disorder (GLPD). In PELs and GLPD the neoplastic cells also contain Epstein-Barr virus (EBV). In addition, occasional cases with atypical and overlapping features among these entities have been recognised, suggesting that the spectrum of the HHV8-related lesions may not be fully characterised. AIMS: Here, we report two cases of lymphoproliferative disorder associated with HHV8 and EBV that further expand the spectrum of HHV8/EBV-positive lymphoproliferative disease. METHODS AND RESULTS: Case 1 represented HHV8/EBV-positive extracavitary nodal PEL followed by pleural PEL. The striking characteristic of this case was the almost focal and intrasinusoidal localisation of the neoplastic cells and the association with Castleman's disease features. In the second case, we found the entire spectrum of HHV8-related disorders, i.e. MCD, GLPD, and PEL, coexisting in the same lymph node, underlining the variability, possible overlap and evolution among these entities. Both cases were well analysed with immunohistochemistry, determination of the EBV latency programme, and molecular analysis for clonality of immnoglobulin genes. In both patients, the disease followed an unexpected indolent course, both being still alive after 8 and 12 months, respectively. CONCLUSION: Our findings represent further evidence of the overlap among HHV8/EBV-positive lymphoproliferative disorders, and underline a grey zone that requires further study; they further confirm the experimental evidence that lytic EBV replication influences HHV8-related tumorigenesis.

Exome sequencing in BRCA1-2 candidate familias: the contribution of other cancer susceptibility genes

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Whole exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate non-canonical genes.

Prognostic impact of tumor-associated macrophages, lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.

INTRODUCTION: Microenvironment has a prognostic influence in diffuse large B-cell lymphoma (DLBCL); among its components, tumor-associated macrophages (TAM) play a leading role. TAM can be classified into M1 (anti-tumor) and M2 (pro-tumor). Another prognostic factor could be represented by lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR). OBJECTIVE: The aim of the study is to evaluate the prognostic impact of M1 and M2 TAM subtypes, LMR and NLR in DLBCL. METHODS: We analyzed 37 consecutive patients between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP/CHOP-like regimens, 9/37 (24.4%) less intensive therapies. Immunohistochemistry was performed with antibodies against CD68 and CD163. We divided our cohort into 2 categories according to the Steidl score. TAM who coexpressed CD68 and CD163 were considered as M2. For LMR and NLR we used previously published cut-offs of 2.71 and 2.81. RESULTS: CR rate was 70.3%; we did not record a significant correlation between CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed a reduced PFS in patients with IPI ≥ 2 and high M2 TAM expression and a trend between higher expression of CD68+ TAM and improved PFS. CONCLUSION: M2 TAM could have a prognostic role for IPI ≥ 2 DLBCL patients receiving R-CHOP, which thus warrants further investigation.

Correction: Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction to: Immune landscape in Burkitt lymphoma reveals M2-macrophage polarization and correlation between PD-L1 expression and non-canonical EBV latency program.

[This corrects the article DOI: 10.1186/s13027-020-00292-w.].

Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas.

The Epstein-Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a "hit-and-run" mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.

Immune landscape in Burkitt lymphoma reveals M2-macrophage polarization and correlation between PD-L1 expression and non-canonical EBV latency program.

BACKGROUND: The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood. METHODS: In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profiling (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by multiple immunohistochemistry (IHC) and multispectral immunofluorescence (IF), we investigated the TME of additional series of 40 BL cases to evaluate the role of the Programmed Death-1 and Programmed Death Ligand-1 (PD-1/PD-L1) immune checkpoint axis. RESULTS: Our results indicate that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non-canonical latency program of EBV with an activated PD-L1 pathway. CONCLUSION: In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets.

Correction to: IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications.

This error was caused due to the author's oversight and this does not change the views or the results presented in the manuscript.