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Badlaeva A, Tregubova A, Asaturova A, Melli B, Cusenza VY, Palicelli A. Hyperthyroidism Associated with Gestational Trophoblastic Neoplasia: Systematic Literature Review and Pathways Analysis. Cancers (Basel) 2025; 17:1398. [PMID: 40361325 PMCID: PMC12071087 DOI: 10.3390/cancers17091398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Background/Objectives: Gestational trophoblastic disease (GTD) is a group of disorders including complete, partial, and invasive/metastatic hydatidiform moles, as well as gestational trophoblastic neoplasia (GTN) (choriocarcinoma; placental site trophoblastic tumor, PSTT; epithelioid trophoblastic tumor, ETT; or mixed forms). These entities are characterized by increased trophoblast proliferation, rarely complicated by hyperthyroidism. Methods: Our systematic literature review (PRISMA guidelines; PubMed, Web of Science, and Scopus databases) searched for histologically confirmed cases of GTN associated with clinical or subclinical hyperthyroidism. We described the clinical-pathologic features and the pathways of hyperthyroidism in GTD. Results: We identified just 32 choriocarcinomas and one PSTT; other non-histologically confirmed cases could have been identified, as some patients received a clinical diagnosis based on serum human chorionic gonadotropin (hCG) levels and imagining data and were treated accordingly. As regards choriocarcinomas, patients' age range was 15-45 (mean 27) years. Metastases involved the lungs (53%), brain (25%), and liver (19%) (less frequently, the kidneys, spleen, ovaries, vagina, pelvis/abdomen, or thyroid). The time to recurrence range was 1-36 (mean 12) months. On follow-up, 10 patients (32%) were alive with disease and 6 (19%) showed no evidence of disease, while most of the women (15 cases, 48%) died of disease. The hCG level range was 10,000-3,058,000,000 (mean 128,957,613) IU/L. At least some symptoms and/or signs of hyperthyroidism were evident with variable intensity in most cases and significantly improved within 2-3 weeks after treatment. Conclusions: Increased trophoblast proliferation could stimulate thyroid function via increasing the half-life of thyroxine-binding globulin. Secondly, increased hCG demonstrates cross-reactivity with the thyroid-stimulating hormone due to similar α-subunits. Moreover, basic isoforms of hCG may facilitate thyrotropic activity.
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Affiliation(s)
- Alina Badlaeva
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia; (A.B.); (A.T.)
| | - Anna Tregubova
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia; (A.B.); (A.T.)
| | - Aleksandra Asaturova
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia; (A.B.); (A.T.)
| | - Beatrice Melli
- Molecular Pathology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (B.M.); (V.Y.C.)
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Vincenza Ylenia Cusenza
- Molecular Pathology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (B.M.); (V.Y.C.)
| | - Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
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de Amorim IFG, Melo CPDS, Pereira RDA, Cunha SM, Zózimo TRDS, Queiroz FR, Peixoto IDO, Lopes LMS, do Amaral LR, Gomes MDS, Oliveira JA, Cândido EB, Salles PGDO, Braga LDC. Association of a CHEK2 somatic variant with tumor microenvironment calprotectin expression predicts platinum resistance in a small cohort of ovarian carcinoma. PLoS One 2025; 20:e0315487. [PMID: 40146757 PMCID: PMC11949324 DOI: 10.1371/journal.pone.0315487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/27/2024] [Indexed: 03/29/2025] Open
Abstract
High-grade serous ovarian cancer (HGSOC) low overall survival rate is often attributed to platinum resistance. Recent studies suggest that the tumor associated-microenvironment (TME) is a determining factor in malignant tumor progression and DNA damage plays a crucial role in this process. Here, we sought to identify platinum resistance biomarkers associating the TME immune profile and the mutational landscape of the homologous repair pathway genes with the HGSOC patients prognosis and response to chemotherapy. Using a decision tree classifier approach, we found that platinum resistant (PR) patients were characterized by the presence of a novel deep intronic variant, the CHEK2 c.319+ 3943A > T, and higher L1 expression (p = 0.016), (100% accuracy). Chek2 protein is an important component of DNA repair and L1, also known as calprotectin, is one component of the neutrophil extracellular traps (NETs) during inflammation, previously suggested as a key contributor to the metastatic process in HGSOC. Also, PD-L2 levels were significantly higher in PR patients positive for this CHEK2 variant (p = 0.048), underscoring the need to explore its potential therapeutic role for this cancer. Our results suggest an interplay between TME and DNA repair variants that results in a multifactorial nature of HGSOC resistance to platinum chemotherapy.
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Affiliation(s)
- Izabela Ferreira Gontijo de Amorim
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
- Curso de Medicina, Faculdade de Minas-FAMINAS, Belo Horizonte, Minas Gerais, Brazil
| | - Carolina Pereira de Souza Melo
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
| | - Ramon de Alencar Pereira
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
| | - Sidnéa Macioci Cunha
- Hospital Luxemburgo, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
- Programa de Pós-graduação em Saúde da Mulher, Departamento de Ginecologia e Obstetrícia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Thalía Rodrigues de Souza Zózimo
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
| | - Fábio Ribeiro Queiroz
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
| | - Iago de Oliveira Peixoto
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
- Programa de Pós-graduação em Biotecnologia, Fundação Ezequiel Dias-FUNED, Belo Horizonte, Minas Gerais, Brazil
| | - Luciana Maria Silva Lopes
- Programa de Pós-graduação em Biotecnologia, Fundação Ezequiel Dias-FUNED, Belo Horizonte, Minas Gerais, Brazil
| | - Laurence Rodrigues do Amaral
- Laboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Campus Patos de Minas, Uberlândia, Minas Gerais, Brazil
| | - Matheus de Souza Gomes
- Laboratório de Bioinformática e Análises Moleculares, Universidade Federal de Uberlândia, Campus Patos de Minas, Uberlândia, Minas Gerais, Brazil
| | - Juliana Almeida Oliveira
- Curso de Medicina, Faculdade de Minas-FAMINAS, Belo Horizonte, Minas Gerais, Brazil
- Programa de Pós-Graduação em Ciências Aplicadas à Cirurgia e à Oftalmologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Eduardo Batista Cândido
- Curso de Medicina, Faculdade de Minas-FAMINAS, Belo Horizonte, Minas Gerais, Brazil
- Programa de Pós-graduação em Saúde da Mulher, Departamento de Ginecologia e Obstetrícia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Paulo Guilherme de Oliveira Salles
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
- Hospital Luxemburgo, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
| | - Letícia da Conceição Braga
- Laboratório de Pesquisa Translacional em Oncologia, Núcleo de Ensino, Pesquisa e Inovação, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil
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Palicelli A, Torricelli F, Tonni G, Bisagni A, Zanetti E, Zanelli M, Medina-Illueca VD, Melli B, Zizzo M, Morini A, Bonasoni MP, Santandrea G, Broggi G, Caltabiano R, Sanguedolce F, Koufopoulos NI, Boutas I, Asaturova A, Aguzzoli L, Mandato VD. Primary Carcinomas of the Episiotomy Scar Site: A Systematic Literature Review. Curr Oncol 2025; 32:65. [PMID: 39996865 PMCID: PMC11854652 DOI: 10.3390/curroncol32020065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/26/2025] Open
Abstract
Episiotomy is a perineal incision enlarging the vaginal opening during labor, preventing severe perineal/vaginal/ano-rectal lacerations. We performed a systematic literature review (PRISMA guidelines; Pubmed, Scopus and Web of Science databases) of primary malignant tumors arising from the episiotomy site. Thirteen primary carcinomas were reported, mainly endometriosis-related histotypes (77%) (nine clear cell, CCC; one endometrioid, EC) with only two vulvar invasive squamous cell carcinomas and one adenoid cystic carcinoma of Bartholin's gland. No sarcomas, melanomas or malignant trophoblastic tumors were described. Endometriosis was associated with tumors or reported in history (62%). Malignant transformation occurred 3 to 27 (mean 16) years after diagnosis of endometriosis. Patients were usually post-/peri-menopausal (eight cases, 61%) (age range: 31-70 years, mean 50). Imaging should exclude distant (0% in our series) or lymph node metastases (three cases, 23%), looking for potential invasion of vagina (five cases, 39%), anus (including sphincter) (four cases, 31%) and/or other deep pelvic soft tissues (five cases, 39%). All patients underwent surgery, except for a CCC-patient (only chemoradiation) subsequently progressing and dying of disease. Adjuvant chemotherapy and/or radiotherapy were administered to five (39%) cases, neoadjuvant therapy to four cases (31%). Globally, three (23%) cases recurred or progressed, and two-thirds (15%) died of disease (1 CCC, 1 EC). Radical surgery with lymph node status evaluation and eventual excision should be performed when possible. Chemotherapy and/or radiotherapy can be considered in an adjuvant and/or neoadjuvant setting (or as only treatment in inoperable patients). However, the role of different treatments should be studied in further larger multicenter series.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (G.S.)
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Gabriele Tonni
- Department of Obstetrics and Neonatology, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (G.S.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (G.S.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (G.S.)
| | | | - Beatrice Melli
- Molecular Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Unit of Obstetrics and Gynecology, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (L.A.); (V.D.M.)
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.Z.); (A.M.)
| | - Andrea Morini
- Surgical Oncology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.Z.); (A.M.)
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (G.S.)
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (G.S.)
| | - Giuseppe Broggi
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia” Anatomic Pathology, University of Catania, 95123 Catania, Italy; (G.B.); (R.C.)
| | - Rosario Caltabiano
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia” Anatomic Pathology, University of Catania, 95123 Catania, Italy; (G.B.); (R.C.)
| | | | - Nektarios I. Koufopoulos
- Second Department of Pathology, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece;
| | - Ioannis Boutas
- Breast Unit, Rea Maternity Hospital, P. Faliro, 17564 Athens, Greece;
| | - Aleksandra Asaturova
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Lorenzo Aguzzoli
- Unit of Obstetrics and Gynecology, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (L.A.); (V.D.M.)
| | - Vincenzo Dario Mandato
- Unit of Obstetrics and Gynecology, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (L.A.); (V.D.M.)
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Guo Y, He X, Liu J, Tan Y, Zhang C, Chen S, Zhang S. The relationship between HYDIN and fallopian tubal cilia loss in patients with epithelial ovarian cancer. Front Oncol 2025; 14:1495753. [PMID: 39850822 PMCID: PMC11754247 DOI: 10.3389/fonc.2024.1495753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/09/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Primary cilia play an important role in the development of cancer by regulating signaling pathways. Several studies have demonstrated that women with BRCA mutations have, on average, 50% fewer ciliated cells compared with general women. However, the role of tubal cilia loss in the development of epithelial ovarian cancer (EOC) remains unclear. Few specific studies have been found in linking HYDIN, a ciliary defect associated gene that encodes HYDIN axonemal central pair apparatus protein, which is involved in the transduction of Hedgehog (Hh) signal and is considered a cancer associated antigen, to ovarian cancer. Therefore, our study aimed to investigate the correlation between HYDIN gene mutations and tubal cilia loss in EOC. Methods A whole exome sequencing (WES), immunohistochemistry (IHC), western blot, and reverse transcription quantitative (RT q) PCR were performed in 80 patients with EOC and 50 cases of non ovarian cancer to detect the mutations and expression of tubal ciliary marker, ciliary morphology, and abnormal rate. Results We found that the incidence of tubal cilia loss was higher in EOC group with decreased expression of HYDIN compared with the control group (P<0.05). Discussion This study suggests that tubal ciliary loss is evident in epithelial fallopian tube carcinoma, and ciliary cells may be involved in the occurrence and development of EOC, and cilia-related gene HYDIN is expected to be a tumor marker for epithelial ovarian cancer.
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Affiliation(s)
- Yuanli Guo
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xinxin He
- Department of Pathology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junfeng Liu
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | | | | | - Shan Chen
- Department of Gynecology, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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Gao X, Lin Y, Zhang J, Jiang X, Wu R, Zhong D. Causal Effects of Valine on Ovarian Cancer: A Bidirectional Mendelian Randomization Analysis. Nutr Cancer 2025; 77:405-413. [PMID: 39745021 DOI: 10.1080/01635581.2024.2445870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/21/2025]
Abstract
BACKGROUND Ovarian cancer is a lethal female cancer with a rising incidence that is often diagnosed late due to a lack of symptoms, affecting survival and quality of life. Studies suggest that dietary factors, especially the levels of branched-chain amino acids such as valine, may influence its development. While valine is essential for metabolism, its specific role in ovarian cancer remains unclear, necessitating further research. METHODS This study aimed to elucidate the causal relationship between valine and OC through a bidirectional Mendelian randomization (MR) approach. Data were sourced from the IEU OpenGWAS project, encompassing genome-wide association statistics for valine (N = 115,048) and OC (Ncase = 1,218, Ncontrol = 198,523) among European participants. Independent genetic variants associated with each phenotype at genome-wide significance were employed as instrumental variables (IVs). The primary analysis utilized the inverse variance weighted (IVW) method for two-sample MR analysis. MR‒Egger regression was applied to adjust for potential pleiotropy, whereas the weighted median method provided robust causal estimates under the assumption of valid IVs. Sensitivity analyses, including leave-one-out (LOO) analysis, heterogeneity tests, and horizontal pleiotropy assessments, were conducted to ensure the robustness of the findings. RESULTS The results revealed a significant causal relationship between valine and OC, identifying valine as a risk factor for OC (p = 0.043, 95% CI = 1.00008-1.00491, OR = 1.00249) in the forward MR analysis. Sensitivity analyses confirmed the absence of heterogeneity (Q_p value >0.05) and horizontal pleiotropy (p > 0.05), and LOO analysis validated the stability of the results. Conversely, reverse MR analysis revealed no causal effect of OC on valine levels (p = 0.875, 95% CI = 0.34125-2.51495, OR = 1.08528). CONCLUSIONS These findings reveal a causal link between high valine levels and an increased OC risk. This research highlights the monitoring of valine levels as a preventive strategy and the significance of valine metabolism in OC. Future studies are needed to investigate the mechanisms and interventions for reducing risk, offering insights for clinical practice and public health initiatives in OC prevention.
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Affiliation(s)
- Xinyan Gao
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yanling Lin
- Department of Obstetrics and Gynecology, Fujian Provincial Hospital, Clinical Medical School of Fujian Medical University, Fuzhou, Fujian, China
| | - Jun Zhang
- Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiaoxiang Jiang
- Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Riping Wu
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Dongta Zhong
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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Roostee S, Ehinger D, Jönsson M, Phung B, Jönsson G, Sjödahl G, Staaf J, Aine M. Tumour immune characterisation of primary triple-negative breast cancer using automated image quantification of immunohistochemistry-stained immune cells. Sci Rep 2024; 14:21417. [PMID: 39271910 PMCID: PMC11399404 DOI: 10.1038/s41598-024-72306-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
The tumour immune microenvironment (TIME) in breast cancer is acknowledged with an increasing role in treatment response and prognosis. With a growing number of immune markers analysed, digital image analysis may facilitate broader TIME understanding, even in single-plex IHC data. To facilitate analyses of the latter an open-source image analysis pipeline, Tissue microarray MArker Quantification (TMArQ), was developed and applied to single-plex stainings for p53, CD3, CD4, CD8, CD20, CD68, FOXP3, and PD-L1 (SP142 antibody) in a 218-patient triple negative breast cancer (TNBC) cohort with complementary pathology scorings, clinicopathological, whole genome sequencing, and RNA-sequencing data. TMArQ's cell counts for analysed immune markers were on par with results from alternative methods and consistent with both estimates from human pathology review, different quantifications and classifications derived from RNA-sequencing as well as known prognostic patterns of immune response in TNBC. The digital cell counts demonstrated how immune markers are coexpressed in the TIME when considering TNBC molecular subtypes and DNA repair deficiency, and how combination of immune status with DNA repair deficiency status can improve the prognostic stratification in chemotherapy treated patients. These results underscore the value and potential of integrating TIME and specific tumour intrinsic alterations/phenotypes for the molecular understanding of TNBC.
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Affiliation(s)
- Suze Roostee
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, 22381, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Daniel Ehinger
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden
- Department of Genetics, Pathology, and Molecular Diagnostics, Skåne University Hospital, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Mats Jönsson
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Bengt Phung
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Göran Jönsson
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Gottfrid Sjödahl
- Department of Genetics, Pathology, and Molecular Diagnostics, Skåne University Hospital, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Johan Staaf
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, 22381, Lund, Sweden.
- Department of Translational Medicine, Lund University, Malmö, Sweden.
| | - Mattias Aine
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.
- Department of Translational Medicine, Lund University, Malmö, Sweden.
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7
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Nishijima A, Oda K, Hasegawa K, Koso T, Asada K, Ikeda Y, Taguchi A, Maeda D, Nagae G, Tsuji S, Tatsuno K, Uehara Y, Kurosaki A, Sato S, Tanikawa M, Sone K, Mori M, Ikemura M, Fujiwara K, Ushiku T, Osuga Y, Aburatani H. Integrated genomic/epigenomic analysis stratifies subtypes of clear cell ovarian carcinoma, highlighting their cellular origin. Sci Rep 2024; 14:18797. [PMID: 39138354 PMCID: PMC11322660 DOI: 10.1038/s41598-024-69796-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 08/08/2024] [Indexed: 08/15/2024] Open
Abstract
The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1-3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes.
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Affiliation(s)
- Akira Nishijima
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Katsutoshi Oda
- Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Takahiro Koso
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Kayo Asada
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan
| | - Ayumi Taguchi
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Daichi Maeda
- Department of Molecular and Cellular Pathology, Kanazawa University, Ishikawa, Japan
| | - Genta Nagae
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Shingo Tsuji
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yuriko Uehara
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Akira Kurosaki
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Sho Sato
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Michihiro Tanikawa
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Mayuyo Mori
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Masako Ikemura
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
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8
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Tonni G, Palicelli A, Bassi MC, Torricelli F, Vacca I, Aguzzoli L, Mandato VD. Gastrointestinal Stromal Tumors (GISTs) Mimicking Primary Ovarian Tumors or Metastasizing to the Ovaries: A Systematic Literature Review. Cancers (Basel) 2024; 16:2305. [PMID: 39001368 PMCID: PMC11240519 DOI: 10.3390/cancers16132305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 06/10/2024] [Accepted: 06/18/2024] [Indexed: 07/16/2024] Open
Abstract
Background: Gastrointestinal stromal tumors (GISTs) are a rare neoplasm, sometimes mimicking primary ovarian tumors (OTs) and/or metastasizing to the ovaries (M-OT). We performed a systematic literature review (SLR) of OTs and M-OTs, investigating differences in recurrence-free and overall survival. Methods: Our SLR was performed according to PRISMA guidelines, searching in Pubmed, Scopus, and Web of Science databases from inception until 21 April 2024. Results: Overall, 59 OTs (Group 1) and 21 M-OTs (Group 2) were retrieved. The absence of residual disease after surgery was achieved significantly in a higher percentage of patients with Group 1 GISTs (91.5%) compared with Group 2 GISTs (57.1%). Chemotherapy was more frequently administered to Group 2 patients (33% vs. 0%). Recurrence and deaths for disease were significantly more frequent in Group 2 than Group 1 cases (54.5% vs. 6.8%, and 37.5% vs. 9.8%, respectively). Conclusions: GISTs can rarely mimic primary ovarian cancers or even more rarely metastasize to the ovaries. Group 1 GISTs occurred in younger women, were not associated with elevated tumor markers, and had a better prognosis. In contrast, Group 2 GISTs occurred in older women, may exhibit elevated tumor markers, and presented a worse prognosis. However, no significant statistical difference for survival between the two studied groups was detected. Computed tomography scans can define the size of GISTs, which correlate to stage and prognostic risk classes. The gold standard treatment is complete surgical resection, which was achieved in almost all cases of Group 1 GISTs and in half of Group 2. Histopathology and immunohistochemistry are essential for the final diagnosis and guide chemotherapy treatment.
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Affiliation(s)
- Gabriele Tonni
- Department of Obstetrics and Neonatology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Azienda USL-IRCCS di Reggio Emilia, Via Amendola 2, 42123 Reggio Emilia, Italy
| | - Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Maria Chiara Bassi
- Senior Librarian, Biblioteca Medica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Federica Torricelli
- Translational Research Laboratory, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Ilaria Vacca
- Department of Obstetrics and Gynecologic Oncology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Lorenzo Aguzzoli
- Department of Obstetrics and Gynecologic Oncology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Vincenzo Dario Mandato
- Department of Obstetrics and Gynecologic Oncology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
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9
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Karseladze AI, Asaturova AV, Kiseleva IA, Badlaeva AS, Tregubova AV, Zaretsky AR, Uvarova EV, Zanelli M, Palicelli A. Androgen Insensitivity Syndrome with Bilateral Gonadal Sertoli Cell Lesions, Sertoli-Leydig Cell Tumor, and Paratesticular Leiomyoma: A Case Report and First Systematic Literature Review. J Clin Med 2024; 13:929. [PMID: 38398243 PMCID: PMC10889606 DOI: 10.3390/jcm13040929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/28/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Androgen insensitivity syndrome (AIS) is a rare Mendelian disorder caused by mutations of the androgen receptor (AR) gene on the long arm of the X chromosome. As a result of the mutation, the receptor becomes resistant to androgens, and hence, karyotypically male patients (46,XY) carry a female phenotype. Their cryptorchid gonads are prone to the development of several types of tumors (germ cell, sex cord stromal, and others). Here, we report a 15-year-old female-looking patient with primary amenorrhea who underwent laparoscopic gonadectomy. Histologically, the patient's gonads showed Sertoli cell hamartomas (SCHs) and adenomas (SCAs) with areas of Sertoli-Leydig cell tumors (SLCTs) and a left-sided paratesticular leiomyoma. Rudimentary Fallopian tubes were also present. The patient's karyotype was 46,XY without any evidence of aberrations. Molecular genetic analysis of the left gonad revealed two likely germline mutations-a pathogenic frameshift deletion in the AR gene (c.77delT) and a likely pathogenic missense variant in the RAC1 gene (p.A94V). Strikingly, no somatic mutations, fusions, or copy number variations were found. We also performed the first systematic literature review (PRISMA guidelines; screened databases: PubMed, Scopus, Web of Science; ended on 7 December 2023) of the reported cases of patients with AIS showing benign or malignant Sertoli cell lesions/tumors in their gonads (n = 225; age: 4-84, mean 32 years), including Sertoli cell hyperplasia (1%), Sertoli cell nodules (6%), SCHs (31%), SCAs (36%), Sertoli cell tumors (SCTs) (16%), and SLCTs (4%). The few cases (n = 14, 6%; six SCAs, four SCTs, two SLCTs, and two SCHs) with available follow-up (2-49, mean 17 months) showed no evidence of disease (13/14, 93%) or died of other causes (1/14, 7%) despite the histological diagnosis. Smooth muscle lesions/proliferations were identified in 19 (8%) cases (including clearly reported rudimentary uterine remnants, 3 cases; leiomyomas, 4 cases). Rudimentary Fallopian tube(s) were described in nine (4%) cases. Conclusion: AIS may be associated with sex cord/stromal tumors and, rarely, mesenchymal tumors such as leiomyomas. True malignant sex cord tumors can arise in these patients. Larger series with longer follow-ups are needed to estimate the exact prognostic relevance of tumor histology in AIS.
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Affiliation(s)
- Apollon I. Karseladze
- Oncopathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Aleksandra V. Asaturova
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Irina A. Kiseleva
- Pediatric Gynecology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Alina S. Badlaeva
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Anna V. Tregubova
- 1st Pathology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Andrew R. Zaretsky
- Department of Molecular Technologies, Research Institute of Translational Medicine, N. I. Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Bldg. 1, Ostrovityanova Street, Moscow 117997, Russia;
| | - Elena V. Uvarova
- Pediatric Gynecology Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, Moscow 117513, Russia
| | - Magda Zanelli
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.Z.)
| | - Andrea Palicelli
- Pathology Unit, Azienda USL—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.Z.)
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10
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de Biase D, Maloberti T, Corradini AG, Rosini F, Grillini M, Ruscelli M, Coluccelli S, Altimari A, Gruppioni E, Sanza V, Turchetti D, Galuppi A, Ferioli M, Giunchi S, Dondi G, Tesei M, Ravegnini G, Abbati F, Rubino D, Zamagni C, De Iaco P, Santini D, Ceccarelli C, Perrone AM, Tallini G, De Leo A. Integrated clinicopathologic and molecular analysis of endometrial carcinoma: Prognostic impact of the new ESGO-ESTRO-ESP endometrial cancer risk classification and proposal of histopathologic algorithm for its implementation in clinical practice. Front Med (Lausanne) 2023; 10:1146499. [PMID: 37064027 PMCID: PMC10098215 DOI: 10.3389/fmed.2023.1146499] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/13/2023] [Indexed: 04/03/2023] Open
Abstract
INTRODUCTION The European Society of Gynecologic Oncology/European Society of Radiation Therapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) committee recently proposed a new risk stratification system for endometrial carcinoma (EC) patients that incorporates clinicopathologic and molecular features. The aim of the study is to compare the new ESGO/ESTRO/ESP risk classification system with the previous 2016 recommendations, evaluating the impact of molecular classification and defining a new algorithm for selecting cases for molecular analysis to assign the appropriate risk class. METHODS The cohort included 211 consecutive EC patients. Immunohistochemistry and next-generation sequencing were used to assign molecular subgroups of EC: POLE mutant (POLE), mismatch repair deficient (MMRd), p53 mutant (p53abn), and no specific molecular profile (NSMP). RESULTS Immuno-molecular analysis was successful in all cases, identifying the four molecular subgroups: 7.6% POLE, 32.2% MMRd, 20.9% p53abn, and 39.3% NSMP. The recent 2020 guidelines showed a 32.7% risk group change compared with the previous 2016 classification system: the reassignment is due to POLE mutations, abnormal p53 expression, and a better definition of lymphovascular space invasion. The 2020 system assigns more patients to lower-risk groups (42.2%) than the 2016 recommendation (25.6%). Considering the 2020 risk classification system that includes the difference between "unknown molecular classification" and "known," the integration of molecular subgroups allowed 6.6% of patients to be recategorized into a different risk class. In addition, the use of the proposed algorithm based on histopathologic parameters would have resulted in a 62.6% reduction in molecular analysis, compared to applying molecular classification to all patients. CONCLUSION Application of the new 2020 risk classification integrating clinicopathologic and molecular parameters provided more accurate identification of low-and high-risk patients, potentially allowing a more specific selection of patients for post-operative adjuvant therapy. The proposed histopathologic algorithm significantly decreases the number of tests needed and could be a promising tool for cost reduction without compromising prognostic stratification.
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Affiliation(s)
- Dario de Biase
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy
| | - Thais Maloberti
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | | | - Francesca Rosini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marco Grillini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Martina Ruscelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Sara Coluccelli
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Annalisa Altimari
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elisa Gruppioni
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Viviana Sanza
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Daniela Turchetti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Unit of Medical Genetics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Galuppi
- Radiation Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Martina Ferioli
- Radiation Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Susanna Giunchi
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giulia Dondi
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marco Tesei
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy
| | - Francesca Abbati
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Daniela Rubino
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Claudio Zamagni
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Pierandrea De Iaco
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Donatella Santini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Claudio Ceccarelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Anna Myriam Perrone
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Tallini
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Antonio De Leo
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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11
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Sharma T, Nisar S, Masoodi T, Macha MA, Uddin S, Akil AAS, Pandita TK, Singh M, Bhat AA. Current and emerging biomarkers in ovarian cancer diagnosis; CA125 and beyond. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 133:85-114. [PMID: 36707207 DOI: 10.1016/bs.apcsb.2022.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Ovarian cancer (OC) is one of the most common causes of cancer-related death in women worldwide. Its five-year survival rates are worse than the two most common gynecological cancers, cervical and endometrial. This is because it is asymptomatic in the early stages and usually detected in the advanced metastasized stage. Thus, survival is increasingly dependent on timely diagnosis. The delay in detection is contributed partly by the occurrence of non-specific clinical symptoms in the early stages and the lack of effective biomarkers and detection approaches. This underlines the need for biomarker identification and clinical validation, enabling earlier diagnosis, effective prognosis, and response to therapy. Apart from the traditional diagnostic biomarkers for OC, several new biomarkers have been delineated using advanced high-throughput molecular approaches in recent years. They are currently being clinically evaluated for their true diagnostic potential. In this chapter, we document the commonly utilized traditional screening markers and recently identified emerging biomarkers in OC diagnosis, focusing on secretory and protein biomarkers. We also briefly reviewed the recent advances and prospects in OC diagnosis.
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Affiliation(s)
- Tarang Sharma
- Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Sabah Nisar
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tariq Masoodi
- Laboratory of Cancer immunology and genetics, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Jammu and Kashmir, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ammira Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tej K Pandita
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX, United States
| | - Mayank Singh
- Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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12
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Miglietta S, Girolimetti G, Marchio L, Sollazzo M, Laprovitera N, Coluccelli S, De Biase D, De Leo A, Santini D, Kurelac I, Iommarini L, Ghelli A, Campana D, Ferracin M, Perrone AM, Gasparre G, Porcelli AM. MicroRNA and Metabolic Profiling of a Primary Ovarian Neuroendocrine Carcinoma Pulmonary-Type Reveals a High Degree of Similarity with Small Cell Lung Cancer. Noncoding RNA 2022; 8:64. [PMID: 36287116 PMCID: PMC9611163 DOI: 10.3390/ncrna8050064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/15/2022] [Accepted: 09/21/2022] [Indexed: 11/25/2022] Open
Abstract
Small cell neuroendocrine carcinoma is most frequently found in the lung (SCLC), but it has been also reported, albeit with a very low incidence, in the ovary. Here, we analyze a case of primary small cell carcinoma of the ovary of pulmonary type (SCCOPT), a rare and aggressive tumor with poor prognosis, whose biology and molecular features have not yet been thoroughly investigated. The patient affected by SCCOPT had a residual tumor following chemotherapy which displayed pronounced similarity with neuroendocrine tumors and lung cancer in terms of its microRNA expression profile and mTOR-downstream activation. By analyzing the metabolic markers of the neoplastic lesion, we established a likely glycolytic signature. In conclusion, this in-depth characterization of SCCOPT could be useful for future diagnoses, possibly aided by microRNA profiling, allowing clinicians to adopt the most appropriate therapeutic strategy.
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Affiliation(s)
- Stefano Miglietta
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
| | - Giulia Girolimetti
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Lorena Marchio
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Manuela Sollazzo
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
| | - Noemi Laprovitera
- Unit of Transplant immunobiology and Advanced Cell Therapy, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Sara Coluccelli
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
| | - Antonio De Leo
- Department of Experimental Diagnostic and Specialized Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Donatella Santini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Ivana Kurelac
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Centro Studi E Ricerca Sulle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
| | - Luisa Iommarini
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Centro Studi E Ricerca Sulle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
| | - Anna Ghelli
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
| | - Davide Campana
- Department of Experimental Diagnostic and Specialized Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Manuela Ferracin
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Department of Experimental Diagnostic and Specialized Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
| | - Anna Myriam Perrone
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Centro Studi E Ricerca Sulle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
- Division of Oncologic Gynecology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Giuseppe Gasparre
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Centro Studi E Ricerca Sulle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
| | - Anna Maria Porcelli
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy
- Center for Applied Biomedical Research (CRBA), University of Bologna, 40138 Bologna, Italy
- Centro Studi E Ricerca Sulle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
- Interdepartmental Center of Industrial Research (CIRI) Life Science and Health Technologies, University of Bologna, 40064 Ozzano dell’Emilia, Italy
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13
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Epithelial ovarian cancer: Review article. Cancer Treat Res Commun 2022; 33:100629. [PMID: 36127285 DOI: 10.1016/j.ctarc.2022.100629] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 12/14/2022]
Abstract
Epithelial ovarian cancer is the second commonest cause of death amongst all gynaecological cancers. Treatment is challenging because almost 75% of cases are diagnosed in advanced stages. Front line treatment with aggressive cytoreduction and adjuvant treatment decides the outcome. Despite the complete response to primary treatment majority will relapse with disease. Treatment options of recurrent disease depends on platinum free interval. Systemic therapy is the mainstay of treatment and secondary cytoreduction may be beneficial in selected patients Newer therapeutic agents are being added in the front line and recurrent setting to improve outcome.
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14
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Prieto-Potin I, Idrovo F, Suárez-Gauthier A, Díaz-Blázquez M, Astilleros-Blanco de Córdova L, Chamizo C, Zazo S, Carvajal N, López-Sánchez A, Pérez-Buira S, Aúz-Alexandre CL, Manso R, Plaza-Sánchez J, de Lucas-López V, Pérez-González N, Martín-Valle S, Cristóbal I, Casado V, García-Foncillas J, Rojo F. Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors. Diagnostics (Basel) 2022; 12:diagnostics12081903. [PMID: 36010253 PMCID: PMC9406465 DOI: 10.3390/diagnostics12081903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/22/2022] [Accepted: 08/03/2022] [Indexed: 11/25/2022] Open
Abstract
Gynecological cancer accounts for an elevated incidence worldwide requiring responsiveness regarding its care. The comprehensive genomic approach agrees with the classification of certain tumor types. We evaluated 49 patients with gynecological tumors undergoing high-throughput sequencing to explore whether identifying alterations in cancer-associated genes could characterize concrete histological subtypes. We performed immune examination and analyzed subsequent clinical impact. We found 220 genomic aberrations mostly distributed as single nucleotide variants (SNV, 77%). Only 3% were classified as variants of strong clinical significance in BRCA1 and BRCA2 of ovarian high-grade serous (HGSC) and uterine endometrioid carcinoma. TP53 and BRCA1 occurred in 72% and 28% of HGSC. Cervical squamous cell carcinoma was entirely HPV-associated and mutations occurred in PIK3CA (60%), as well as in uterine serous carcinoma (80%). Alterations were seen in PTEN (71%) and PIK3CA (60%) of uterine endometrioid carcinoma. Elevated programmed death-ligand 1 (PD-L1) was associated with high TILs. Either PD-L1 augmented in deficient mis-matched repair (MMR) proteins or POLE mutated cases when compared to a proficient MMR state. An 18% received genotype-guided therapy and a 4% immunotherapy. The description of tumor subtypes is plausible through high-throughput sequencing by recognizing clinically relevant alterations. Additional concomitant assessment of immune biomarkers identifies candidates for immunotherapy.
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Affiliation(s)
- Iván Prieto-Potin
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Franklin Idrovo
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Ana Suárez-Gauthier
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - María Díaz-Blázquez
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | | | - Cristina Chamizo
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Sandra Zazo
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Nerea Carvajal
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Almudena López-Sánchez
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Sandra Pérez-Buira
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Carmen Laura Aúz-Alexandre
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Rebeca Manso
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Jenifer Plaza-Sánchez
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Virginia de Lucas-López
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Nuria Pérez-González
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Sara Martín-Valle
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Ion Cristóbal
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
- Translational Oncology Division, Oncohealth Institute, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Victoria Casado
- Translational Oncology Division, Oncohealth Institute, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Jesús García-Foncillas
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
- Translational Oncology Division, Oncohealth Institute, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
| | - Federico Rojo
- Department of Pathology, CIBERONC, UAM, Fundación Jiménez Díaz University Hospital Health Research Institute, 28040 Madrid, Spain
- Correspondence:
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15
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Primary ovarian cancer after colorectal cancer: a Dutch nationwide population-based study. Int J Colorectal Dis 2022; 37:1593-1599. [PMID: 35697933 DOI: 10.1007/s00384-022-04184-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND PURPOSE Women with colorectal cancer (CRC) are at risk not only of developing ovarian metastases, but also of developing a primary ovarian malignancy. Several earlier studies have in fact shown a link between the development of primary ovarian cancer and CRC. The purpose of this study was therefore to determine the risk of developing a primary ovarian cancer in women with prior CRC compared to the general population. METHODS Data from the Netherlands Cancer Registry were used. All women diagnosed with invasive CRC between 1989 and 2017 were included. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) per 10,000 person-years were calculated. RESULTS During the study period, 410 (0.3%) CRC patients were diagnosed with primary ovarian cancer. Women with CRC had a 20% increased risk of developing ovarian cancer compared to the general population (SIR = 1.2, 95% CI: 1.1-1.3). The AER of ovarian cancer was 0.9 per 10,000 person-years. The risk was especially increased within the first year of a CRC diagnosis (SIR = 3.3, 95% CI: 2.8-3.8) and in women aged ≤ 55 years (SIR = 2.0, 95% CI: 1.6-2.6). CONCLUSION This study found a slightly increased risk of primary ovarian cancer in women diagnosed with CRC compared to the general population. However, this may be partly attributable to surveillance or detection bias. Nevertheless, our findings could be helpful for patient counseling, as CRC patients do not currently receive information concerning the increased risk of ovarian cancer.
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Mandato VD, Palicelli A, Torricelli F, Mastrofilippo V, Leone C, Dicarlo V, Tafuni A, Santandrea G, Annunziata G, Generali M, Pirillo D, Ciarlini G, Aguzzoli L. Should Endometrial Cancer Treatment Be Centralized? BIOLOGY 2022; 11:768. [PMID: 35625496 PMCID: PMC9138425 DOI: 10.3390/biology11050768] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 05/17/2023]
Abstract
Endometrial cancer (EC) is the most common malignancy of the female genital tract in Western and emerging countries. In 2012, new cancer cases numbered 319,605, and 76,160 cancer deaths were diagnosed worldwide. ECs are usually diagnosed after menopause; 70% of ECs are diagnosed at an early stage with a favorable prognosis and a 5-year overall survival rate of 77%. On the contrary, women with advanced or recurrent disease have extremely poor outcomes because they show a low response rate to conventional chemotherapy. EC is generally considered easy to treat, although it presents a 5-year mortality of 25%. Though the guidelines (GLs) recommend treatment in specialized centers by physicians specializing in gynecologic oncology, most women are managed by general gynecologists, resulting in differences and discrepancies in clinical management. In this paper we reviewed the literature with the aim of highlighting where the treatment of EC patients requires gynecologic oncologists, as suggested by the GLs. Moreover, we sought to identify the causes of the lack of GL adherence, suggesting useful changes to ensure adequate treatment for all EC patients.
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Affiliation(s)
- Vincenzo Dario Mandato
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (A.P.); (A.T.); (G.S.)
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy;
| | - Valentina Mastrofilippo
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Chiara Leone
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Vittoria Dicarlo
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Alessandro Tafuni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (A.P.); (A.T.); (G.S.)
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (A.P.); (A.T.); (G.S.)
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Gianluca Annunziata
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Matteo Generali
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Debora Pirillo
- Unit of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (V.M.); (C.L.); (V.D.); (G.A.); (M.G.); (D.P.)
| | - Gino Ciarlini
- Unit of Surgical Gynecol Oncology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.C.); (L.A.)
| | - Lorenzo Aguzzoli
- Unit of Surgical Gynecol Oncology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.C.); (L.A.)
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S-100 Immunohistochemical Positivity in Rhabdomyoma: An Underestimated Potential Diagnostic Pitfall in Routine Practice. Diagnostics (Basel) 2022; 12:diagnostics12040892. [PMID: 35453940 PMCID: PMC9030831 DOI: 10.3390/diagnostics12040892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 02/04/2023] Open
Abstract
A 66-year-old man presented with a 2.8 cm lesion of the left vocal cord. On contrast-enhanced computed tomography scans, the tumor extended to the supraglottis, subglottis, paraglottic space and anterior commissure, causing partial obstruction of the laryngeal lumen. At another hospital, a fragmented incisional biopsy was diagnosed as a granular cell tumor, as to the S-100 immunohistochemical positivity. After excision, the tumor revealed to be an adult-type laryngeal rhabdomyoma. The typical cytoplasmic rod-like inclusions and cross striations were more evident in the second specimen. We confirmed the unusual S-100 immunohistochemical positivity (variable intensity, >90% of tumor cells). Muscle markers were not performed on the previous biopsy, resulting positive in our specimen (Desmin: strong, diffuse expression; Smooth Muscle Actin: strong staining in 10% of tumor cells). Melan-A, CD68, GFAP, pan-cytokeratins, CEA, calretinin and neurofilaments resulted negative. To our brief, systematic literature review, S-100 positivity (usually variable, often weak or patchy/focal) was globally found in 19/34 (56%) adult-type rhabdomyomas of the head and neck region. Especially on fragmented biopsy material, the differential diagnoses of laryngeal rhabdomyomas may include granular cell tumors, oncocytic tumors of the salivary glands or of different origin, and paragangliomas.
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De Leo A, Ravegnini G, Musiani F, Maloberti T, Visani M, Sanza V, Angelini S, Perrone AM, De Iaco P, Corradini AG, Rosini F, Grillini M, Santini D, Ceccarelli C, Zamagni C, Tallini G, de Biase D. Relevance of ARID1A Mutations in Endometrial Carcinomas. Diagnostics (Basel) 2022; 12:592. [PMID: 35328145 PMCID: PMC8947028 DOI: 10.3390/diagnostics12030592] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 02/21/2022] [Indexed: 02/05/2023] Open
Abstract
Since the Cancer Genome Atlas (TCGA) project identified four distinct groups based on molecular alterations, mutation analyses have been integrated into the characterization of endometrial carcinomas (ECs). ARID1A seems to be the subunit more involved in the loss of function of the SWI/SNF complex in ECs. The aim of this study is to define the relevance of ARID1A alterations in a cohort of EC, studying the possible associations between DNA mutation (genomic level), RNA expression (transcriptomic level), and protein expression (proteomic level). A total of 50 endometrial carcinomas were characterized for ARID1A mutations (using targeted DNA next-generation sequencing-NGS), ARID1A gene expression (using RNAseq and qRT-PCR), and ARID1A protein expression (using immunohistochemistry-IHC). Moreover, we have investigated if ARID1A mutations may alter the protein structure, using the Protein Data Bank sequence. We found a good correlation between ARID1A mutations and protein immunostaining, even if we did not find statistically significant differences in the ARID1A expression levels. In conclusion, our data demonstrated that the molecular characterization of ARID1A should be associated with IHC analysis, mainly in those cases harboring "novel" ARID1A mutations or in those alterations with "uncertain" pathogenic significance.
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Affiliation(s)
- Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna-Molecular Diagnostic Unit, Azienda USL di Bologna, 40138 Bologna, Italy; (A.D.L.); (T.M.); (M.V.); (G.T.)
- Division of Molecular Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, 40127 Bologna, Italy; (G.R.); (S.A.)
| | - Francesco Musiani
- Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, 40127 Bologna, Italy;
| | - Thais Maloberti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna-Molecular Diagnostic Unit, Azienda USL di Bologna, 40138 Bologna, Italy; (A.D.L.); (T.M.); (M.V.); (G.T.)
| | - Michela Visani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna-Molecular Diagnostic Unit, Azienda USL di Bologna, 40138 Bologna, Italy; (A.D.L.); (T.M.); (M.V.); (G.T.)
| | - Viviana Sanza
- Division of Molecular Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, 40127 Bologna, Italy; (G.R.); (S.A.)
| | - Anna Myriam Perrone
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.P.); (P.D.I.)
- Department of Medical and Surgical Sciences (DIMEC)-Centro di Studio e Ricerca delle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
| | - Pierandrea De Iaco
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.P.); (P.D.I.)
- Department of Medical and Surgical Sciences (DIMEC)-Centro di Studio e Ricerca delle Neoplasie Ginecologiche (CSR), University of Bologna, 40138 Bologna, Italy
| | - Angelo Gianluca Corradini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.G.C.); (F.R.); (M.G.); (D.S.)
| | - Francesca Rosini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.G.C.); (F.R.); (M.G.); (D.S.)
| | - Marco Grillini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.G.C.); (F.R.); (M.G.); (D.S.)
| | - Donatella Santini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.G.C.); (F.R.); (M.G.); (D.S.)
| | - Claudio Ceccarelli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy;
| | - Claudio Zamagni
- Addarii Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna-Molecular Diagnostic Unit, Azienda USL di Bologna, 40138 Bologna, Italy; (A.D.L.); (T.M.); (M.V.); (G.T.)
- Division of Molecular Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna-Molecular Diagnostic Unit, 40138 Bologna, Italy
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Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, Cañete-Portillo S, Bonasoni MP, Ascani S, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Gandhi J, Nicoli D, Farnetti E, Piana S, Tafuni A, Bonacini M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes. Biomedicines 2022; 10:236. [PMID: 35203446 PMCID: PMC8868626 DOI: 10.3390/biomedicines10020236] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 01/21/2022] [Indexed: 02/05/2023] Open
Abstract
Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asuncion 1614, Paraguay;
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Davide Nicoli
- Molecular Biology Laboratory, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (D.N.); (E.F.)
| | - Enrico Farnetti
- Molecular Biology Laboratory, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (D.N.); (E.F.)
| | - Simonetta Piana
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
| | - Alessandro Tafuni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (S.P.); (A.T.)
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
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20
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The Evolution of Ovarian Carcinoma Subclassification. Cancers (Basel) 2022; 14:cancers14020416. [PMID: 35053578 PMCID: PMC8774015 DOI: 10.3390/cancers14020416] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Historically, cancers presenting with their main tumor mass in the ovary have been classified as ovarian carcinomas (a concise term for epithelial ovarian cancer) and treated with a one-size-fits-all approach. Over the last two decades, a growing molecular understanding established that ovarian carcinomas consist of several distinct histologic types, which practically represent different diseases. Further research is now delineating several molecular subtypes within each histotype. This histotype/molecular subtype subclassification provides a framework of grouping tumors based on molecular similarities for research, clinical trial inclusion and future patient management. Abstract The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas.
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Palicelli A, Bonacini M, Croci S, Bisagni A, Zanetti E, De Biase D, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, Cañete-Portillo S, Bonasoni MP, Ascani S, De Leo A, Gandhi J, Tafuni A, Melli B. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy. J Pers Med 2021; 11:1312. [PMID: 34945784 PMCID: PMC8709072 DOI: 10.3390/jpm11121312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 02/05/2023] Open
Abstract
Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.)
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.B.); (S.C.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.B.); (S.C.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay;
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.)
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Alessandro Tafuni
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
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Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, Cañete-Portillo S, Bonasoni MP, Soriano A, Ascani S, Zizzo M, Castro Ruiz C, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Berney DM, Gandhi J, Nicoli D, Farnetti E, Santandrea G, Bonacini M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1. Int J Mol Sci 2021; 22:12314. [PMID: 34830196 PMCID: PMC8619683 DOI: 10.3390/ijms222212314] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/18/2021] [Accepted: 10/22/2021] [Indexed: 02/05/2023] Open
Abstract
Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay;
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Carolina Castro Ruiz
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Daniel M. Berney
- Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK;
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Davide Nicoli
- Molecular Biology Laboratory, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (D.N.); (E.F.)
| | - Enrico Farnetti
- Molecular Biology Laboratory, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (D.N.); (E.F.)
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
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Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, Cañete-Portillo S, Bonasoni MP, Soriano A, Ascani S, Zizzo M, Castro Ruiz C, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Berney DM, Gandhi J, Copelli V, Bernardelli G, Santandrea G, Bonacini M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment. Int J Mol Sci 2021; 22:12330. [PMID: 34830209 PMCID: PMC8618001 DOI: 10.3390/ijms222212330] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Centre, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay;
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Carolina Castro Ruiz
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Daniel M. Berney
- Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK;
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Valerio Copelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Giuditta Bernardelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (V.C.); (G.B.); (G.S.)
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
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Palicelli A, Bonacini M, Croci S, Magi-Galluzzi C, Cañete-Portillo S, Chaux A, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Bonasoni MP, Soriano A, Ascani S, Zizzo M, Castro Ruiz C, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Berney DM, Athanazio D, Gandhi J, Cavazza A, Santandrea G, Tafuni A, Zanelli M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables. Cells 2021; 10:3166. [PMID: 34831389 PMCID: PMC8625301 DOI: 10.3390/cells10113166] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/25/2021] [Accepted: 11/05/2021] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy targeting the PD-1-PD-L1 axis yielded good results in treating different immunologically ''hot'' tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11-41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in <200 cases. The PD-L1 positivity rate was usually higher in tumors than benign tissues. It was higher in non-tissue microarray specimens (41-50% vs. 15%), as PC cells frequently showed heterogenous or focal PD-L1-staining. PD-L1 was expressed by immune or stromal cells in 12% and 69% cases, respectively. Tumor heterogeneity, inter-institutional preanalytics, and inter-observer interpretation variability may account for result biases.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.B.); (S.C.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.B.); (S.C.)
| | - Cristina Magi-Galluzzi
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (C.M.-G.); (S.C.-P.)
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (C.M.-G.); (S.C.-P.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies Norte University, Asunción 1614, Paraguay;
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Carolina Castro Ruiz
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Daniel M. Berney
- Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK;
| | | | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Alberto Cavazza
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Alessandro Tafuni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.P.B.); (A.C.); (G.S.); (A.T.); (M.Z.)
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Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Ragazzi M, Zanelli M, Chaux A, Cañete-Portillo S, Bonasoni MP, Soriano A, Ascani S, Zizzo M, Castro Ruiz C, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Berney DM, Gandhi J, Santandrea G, Bonacini M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models). Int J Mol Sci 2021; 22:12297. [PMID: 34830179 PMCID: PMC8618402 DOI: 10.3390/ijms222212297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 02/05/2023] Open
Abstract
In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- International Doctorate School in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | | | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay;
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Carolina Castro Ruiz
- International Doctorate School in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy;
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Daniel M. Berney
- Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK;
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.R.); (M.Z.); (M.P.B.); (G.S.)
- International Doctorate School in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (S.C.); (M.B.)
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Palicelli A, Bonacini M, Croci S, Magi-Galluzzi C, Cañete-Portillo S, Chaux A, Bisagni A, Zanetti E, De Biase D, Melli B, Sanguedolce F, Zanelli M, Bonasoni MP, De Marco L, Soriano A, Ascani S, Zizzo M, Castro Ruiz C, De Leo A, Giordano G, Landriscina M, Carrieri G, Cormio L, Berney DM, Gandhi J, Santandrea G, Gelli MC, Tafuni A, Ragazzi M. What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic-Pathologic Correlations. Cells 2021; 10:3165. [PMID: 34831388 PMCID: PMC8618408 DOI: 10.3390/cells10113165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 02/08/2023] Open
Abstract
Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic-pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.B.); (S.C.)
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (M.B.); (S.C.)
| | - Cristina Magi-Galluzzi
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (C.M.-G.); (S.C.-P.)
| | - Sofia Cañete-Portillo
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (C.M.-G.); (S.C.-P.)
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción 1614, Paraguay;
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Dario De Biase
- Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy;
| | - Beatrice Melli
- Fertility Center, Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | | | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Loredana De Marco
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;
- Haematopathology Unit, CREO, Azienda Ospedaliera di Perugia, University of Perugia, 06129 Perugia, Italy
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Carolina Castro Ruiz
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Guido Giordano
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Matteo Landriscina
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.G.); (M.L.)
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University of Foggia, 71122 Foggia, Italy; (G.C.); (L.C.)
| | - Daniel M. Berney
- Barts Cancer Institute, Queen Mary University of London, London EC1M 5PZ, UK;
| | - Jatin Gandhi
- Department of Pathology and Laboratory Medicine, University of Washington, Seattle, WA 98195, USA;
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Maria Carolina Gelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
| | - Alessandro Tafuni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy
| | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.B.); (E.Z.); (M.Z.); (M.P.B.); (L.D.M.); (G.S.); (M.C.G.); (A.T.); (M.R.)
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Radu MR, Prădatu A, Duică F, Micu R, Creţoiu SM, Suciu N, Creţoiu D, Varlas VN, Rădoi VE. Ovarian Cancer: Biomarkers and Targeted Therapy. Biomedicines 2021; 9:693. [PMID: 34207450 PMCID: PMC8235073 DOI: 10.3390/biomedicines9060693] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 12/25/2022] Open
Abstract
Ovarian cancer is one of the most common causes of death in women as survival is highly dependent on the stage of the disease. Ovarian cancer is typically diagnosed in the late stage due to the fact that in the early phases is mostly asymptomatic. Genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. Early detection of the disorder is one of the most important steps that facilitate a favorable prognosis and a good response to medical therapy for the patients. In targeted therapies, individual patients are treated by agents targeting the changes in tumor cells that help them grow, divide and spread. Currently, in gynecological malignancies, potential therapeutic targets include tumor-intrinsic signaling pathways, angiogenesis, homologous-recombination deficiency, hormone receptors, and immunologic factors. Ovarian cancer is usually diagnosed in the final stages, partially due to the absence of an effective screening strategy, although, over the times, numerous biomarkers have been studied and used to assess the status, progression, and efficacy of the drug therapy in this type of disorder.
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Affiliation(s)
- Mihaela Raluca Radu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
| | - Alina Prădatu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
| | - Florentina Duică
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
| | - Romeo Micu
- Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Sanda Maria Creţoiu
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Nicolae Suciu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, 020395 Bucharest, Romania;
| | - Dragoş Creţoiu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Valentin Nicolae Varlas
- Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, 01171 Bucharest, Romania
- Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 030167 Bucharest, Romania
| | - Viorica Elena Rădoi
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, 020395 Bucharest, Romania;
- Department of Medical Genetics, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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De Leo A, Santini D, Ceccarelli C, Santandrea G, Palicelli A, Acquaviva G, Chiarucci F, Rosini F, Ravegnini G, Pession A, Turchetti D, Zamagni C, Perrone AM, De Iaco P, Tallini G, de Biase D. What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors. Diagnostics (Basel) 2021; 11:697. [PMID: 33919741 PMCID: PMC8070731 DOI: 10.3390/diagnostics11040697] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/05/2021] [Accepted: 04/10/2021] [Indexed: 02/05/2023] Open
Abstract
Ovarian carcinomas represent a heterogeneous group of neoplasms consisting of separate entities with distinct risk factors, precursor lesions, pathogenesis, patterns of spread, molecular profiles, clinical course, response to chemotherapy, and outcomes. The histologic subtype and the related molecular features are essential for individualized clinical decision-making. The fifth edition of the World Health Organization classification of tumors of the female genital tract divides ovarian carcinomas into at least five main and distinct types of ovarian carcinomas: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. Molecular pathology has improved the knowledge of genomic landscape of ovarian carcinomas identifying peculiar alterations for every histologic subtype. It is well-known that high-grade and low-grade serous carcinomas are separate entities with entirely different morphologic and molecular characteristics. TP53 and BRCA mutations are typical of high-grade serous carcinoma, whereas BRAF and KRAS mutations frequently occur in low-grade serous carcinoma. Endometrioid and clear cell carcinomas are frequently associated with endometriosis. Endometrioid tumors are characterized by β-catenin alterations, microsatellite instability, and PTEN and POLE mutations, while ARID1A mutations occur in both endometrioid and clear cell carcinomas. Mucinous carcinomas are uncommon tumors associated with copy-number loss of CDKN2A and KRAS alterations and metastasis from other sites should always be considered in the differential diagnosis.
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Affiliation(s)
- Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum—University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (G.A.); (F.C.); (G.T.)
- Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero—Universitaria di Bologna/Azienda USL di Bologna, 40138 Bologna, Italy; (A.P.); (D.d.B.)
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
| | - Donatella Santini
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
- Pathology Unit, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy;
| | - Claudio Ceccarelli
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum—University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (G.A.); (F.C.); (G.T.)
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
| | - Giacomo Santandrea
- Pathology Unit, AUSL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.S.); (A.P.)
| | - Andrea Palicelli
- Pathology Unit, AUSL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.S.); (A.P.)
| | - Giorgia Acquaviva
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum—University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (G.A.); (F.C.); (G.T.)
- Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero—Universitaria di Bologna/Azienda USL di Bologna, 40138 Bologna, Italy; (A.P.); (D.d.B.)
| | - Federico Chiarucci
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum—University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (G.A.); (F.C.); (G.T.)
- Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero—Universitaria di Bologna/Azienda USL di Bologna, 40138 Bologna, Italy; (A.P.); (D.d.B.)
| | - Francesca Rosini
- Pathology Unit, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy;
| | - Gloria Ravegnini
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Annalisa Pession
- Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero—Universitaria di Bologna/Azienda USL di Bologna, 40138 Bologna, Italy; (A.P.); (D.d.B.)
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Daniela Turchetti
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
- Unit of Medical Genetics, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Claudio Zamagni
- IRCCS Azienda Ospedaliero—Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy;
| | - Anna Myriam Perrone
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Via Massarenti 13, 40138 Bologna, Italy
| | - Pierandrea De Iaco
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
- Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero—Universitaria di Bologna, Via Massarenti 13, 40138 Bologna, Italy
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum—University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (C.C.); (G.A.); (F.C.); (G.T.)
- Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero—Universitaria di Bologna/Azienda USL di Bologna, 40138 Bologna, Italy; (A.P.); (D.d.B.)
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
| | - Dario de Biase
- Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero—Universitaria di Bologna/Azienda USL di Bologna, 40138 Bologna, Italy; (A.P.); (D.d.B.)
- Centro di Studio e Ricerca delle Neoplasie Ginecologiche, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy; (D.S.); (G.R.); (D.T.); (A.M.P.); (P.D.I.)
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
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Palicelli A, Giaccherini L, Zanelli M, Bonasoni MP, Gelli MC, Bisagni A, Zanetti E, De Marco L, Torricelli F, Manzotti G, Gugnoni M, D’Ippolito G, Falbo AI, Sileo FG, Aguzzoli L, Mastrofilippo V, Bonacini M, De Giorgi F, Ricci S, Bernardelli G, Ardighieri L, Zizzo M, De Leo A, Santandrea G, de Biase D, Ragazzi M, Dalla Dea G, Veggiani C, Carpenito L, Sanguedolce F, Asaturova A, Boldorini R, Disanto MG, Goia M, Wong RWC, Singh N, Mandato VD. How Can We Treat Vulvar Carcinoma in Pregnancy? A Systematic Review of the Literature. Cancers (Basel) 2021; 13:836. [PMID: 33671249 PMCID: PMC7921964 DOI: 10.3390/cancers13040836] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/06/2021] [Accepted: 02/11/2021] [Indexed: 02/05/2023] Open
Abstract
According to our systematic literature review (PRISMA guidelines), only 37 vulvar squamous cell carcinomas (VSCCs) were diagnosed during pregnancy (age range: 17-41 years). The tumor size range was 0.3-15 cm. The treatment was performed after (14/37, 38%), before (10/37, 27%), or before-and-after delivery (11/37, 30%). We found that 21/37 (57%) cases were stage I, 2 II (5%), 11 III (30%), and 3 IVB (8%). HPV-related features (condylomas/warts; HPV infection; high-grade squamous intraepithelial lesion) were reported in 11/37 (30%) cases. We also found that 9/37 (24%) patients had inflammatory conditions (lichen sclerosus/planus, psoriasis, chronic dermatitis). The time-to-recurrence/progression (12/37, 32%) ranged from 0 to 36 (mean 9) months. Eight women died of disease (22%) 2.5-48 months after diagnosis, 2 (5%) were alive with disease, and 23 (62%) were disease-free at the end of follow-up. Pregnant patients must be followed-up. Even if they are small, newly arising vulvar lesions should be biopsied, especially in women with risk factors (HPV, dermatosis, etc.). The treatment of VSCCs diagnosed in late third trimester might be delayed until postpartum. Elective cesarean section may prevent vulvar wound dehiscence. In the few reported cases, pregnancy/fetal outcomes seemed to not be affected by invasive treatments during pregnancy. However, clinicians must be careful; larger cohorts should define the best treatment. Definite guidelines are lacking, so a multidisciplinary approach and discussion with patients are mandatory.
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Affiliation(s)
- Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Lucia Giaccherini
- Radiation Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy;
| | - Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Maria Paola Bonasoni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Maria Carolina Gelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Alessandra Bisagni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Loredana De Marco
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (F.T.); (G.M.); (M.G.)
| | - Gloria Manzotti
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (F.T.); (G.M.); (M.G.)
| | - Mila Gugnoni
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (F.T.); (G.M.); (M.G.)
| | - Giovanni D’Ippolito
- Unit of Obstetrics and Gynaecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.D.); (A.I.F.); (F.G.S.); (V.D.M.)
| | - Angela Immacolata Falbo
- Unit of Obstetrics and Gynaecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.D.); (A.I.F.); (F.G.S.); (V.D.M.)
| | - Filomena Giulia Sileo
- Unit of Obstetrics and Gynaecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.D.); (A.I.F.); (F.G.S.); (V.D.M.)
| | - Lorenzo Aguzzoli
- Unit of Surgical Gynecol Oncology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (L.A.); (V.M.)
| | - Valentina Mastrofilippo
- Unit of Surgical Gynecol Oncology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (L.A.); (V.M.)
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy;
| | - Federica De Giorgi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Stefano Ricci
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Giuditta Bernardelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Laura Ardighieri
- Pathology Unit, ASST Spedali Civili di Brescia, 25123 Brescia, Italy;
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Antonio De Leo
- Molecular Diagnostic Unit, Azienda USL Bologna, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy;
| | - Giacomo Santandrea
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Dario de Biase
- Pharmacology and Biotechnology Department (FaBiT), University of Bologna, 40138 Bologna, Italy;
| | - Moira Ragazzi
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (M.Z.); (M.P.B.); (M.C.G.); (A.B.); (E.Z.); (L.D.M.); (F.D.G.); (S.R.); (G.B.); (G.S.); (M.R.)
| | - Giulia Dalla Dea
- Department of Health Science, University of Eastern Piedmont, 28100 Novara, Italy; (G.D.D.); (R.B.)
- Pathology Unit, Maggiore Della Carità Hospital, 28100 Novara, Italy;
| | - Claudia Veggiani
- Pathology Unit, Maggiore Della Carità Hospital, 28100 Novara, Italy;
| | - Laura Carpenito
- School of Pathology, University of Milan, 20122 Milan, Italy;
| | - Francesca Sanguedolce
- Pathology Unit, Azienda Ospedaliero-Universitaria-Ospedali Riuniti di Foggia, 71122 Foggia, Italy;
| | - Aleksandra Asaturova
- 1st Pathology Department, FSBI “National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov”, Ministry of Healthcare of the Russian Federation, 117997 Moscow, Russia;
| | - Renzo Boldorini
- Department of Health Science, University of Eastern Piedmont, 28100 Novara, Italy; (G.D.D.); (R.B.)
- Pathology Unit, Maggiore Della Carità Hospital, 28100 Novara, Italy;
| | | | - Margherita Goia
- Unit of Pathology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy;
| | - Richard Wing-Cheuk Wong
- Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China;
| | - Naveena Singh
- Department of Cellular Pathology, Barts Health NHS Trust, The Royal London Hospital, Whitechapel, London E1 1BB, UK;
| | - Vincenzo Dario Mandato
- Unit of Obstetrics and Gynaecology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (G.D.); (A.I.F.); (F.G.S.); (V.D.M.)
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