Journal of Personalized Medicine (Apr 2022)
Validation of a Novel Three-Dimensional (<i>3D Fusion</i>) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study
- Matteo Brunelli,
- Guido Martignoni,
- Giorgio Malpeli,
- Alessandro Volpe,
- Luca Cima,
- Maria Rosaria Raspollini,
- Mattia Barbareschi,
- Alessandro Tafuri,
- Giulia Masi,
- Luisa Barzon,
- Serena Ammendola,
- Manuela Villanova,
- Maria Angela Cerruto,
- Michele Milella,
- Sebastiano Buti,
- Melissa Bersanelli,
- Giuseppe Fornarini,
- Sara Elena Rebuzzi,
- Valerio Gaetano Vellone,
- Gabriele Gaggero,
- Giuseppe Procopio,
- Elena Verzoni,
- Sergio Bracarda,
- Martina Fanelli,
- Roberto Sabbatini,
- Rodolfo Passalacqua,
- Bruno Perrucci,
- Maria Olga Giganti,
- Maddalena Donini,
- Stefano Panni,
- Marcello Tucci,
- Veronica Prati,
- Cinzia Ortega,
- Anna Caliò,
- Albino Eccher,
- Filippo Alongi,
- Giovanni Pappagallo,
- Roberto Iacovelli,
- Alessandra Mosca,
- Paolo Umari,
- Ilaria Montagnani,
- Stefano Gobbo,
- Francesco Atzori,
- Enrico Munari,
- Marco Maruzzo,
- Umberto Basso,
- Francesco Pierconti,
- Carlo Patriarca,
- Piergiuseppe Colombo,
- Alberto Lapini,
- Giario Conti,
- Roberto Salvioni,
- Enrico Bollito,
- Andrea Cossarizza,
- Francesco Massari,
- Mimma Rizzo,
- Renato Franco,
- Federica Zito-Marino,
- Yoseba Aberasturi Plata,
- Francesca Galuppini,
- Marta Sbaraglia,
- Matteo Fassan,
- Angelo Paolo Dei Tos,
- Maurizio Colecchia,
- Holger Moch,
- Maurizio Scaltriti,
- Camillo Porta,
- Brett Delahunt,
- Gianluca Giannarini,
- Roberto Bortolus,
- Pasquale Rescigno,
- Giuseppe Luigi Banna,
- Alessio Signori,
- Miguel Angel Llaja Obispo,
- Roberto Perris,
- Alessandro Antonelli
Affiliations
- Matteo Brunelli
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
- Guido Martignoni
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
- Giorgio Malpeli
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37134 Verona, Italy
- Alessandro Volpe
- Division of Urology, Maggiore della Carità Hospital, 28100 Novara, Italy
- Luca Cima
- Pathology Unit, Department of Clinical Services, Santa Chiara Hospital, 38100 Trento, Italy
- Maria Rosaria Raspollini
- Histopathology and Molecular Diagnostics, University Hospital Careggi, 50100 Firenze, Italy
- Mattia Barbareschi
- Pathology Unit, Department of Clinical Services, Santa Chiara Hospital, 38100 Trento, Italy
- Alessandro Tafuri
- Division of Urology, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University and Hospital Trust of Verona, 37134 Verona, Italy
- Giulia Masi
- Department of Molecular Medicine, University of Padua, 35100 Padova, Italy
- Luisa Barzon
- Department of Molecular Medicine, University of Padua, 35100 Padova, Italy
- Serena Ammendola
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
- Manuela Villanova
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
- Maria Angela Cerruto
- Division of Urology, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University and Hospital Trust of Verona, 37134 Verona, Italy
- Michele Milella
- Division of Oncology, University and Hospital Trust of Verona, 37134 Verona, Italy
- Sebastiano Buti
- Division of Oncology, University and Hospital Trust of Parma, 43100 Parma, Italy
- Melissa Bersanelli
- Division of Oncology, University and Hospital Trust of Parma, 43100 Parma, Italy
- Giuseppe Fornarini
- Division of Oncology, San Martino Hospital, 16100 Genova, Italy
- Sara Elena Rebuzzi
- Division of Oncology, San Martino Hospital, 16100 Genova, Italy
- Valerio Gaetano Vellone
- Pathology Unit, San Martino Hospital, 16100 Genova, Italy
- Gabriele Gaggero
- Pathology Unit, San Martino Hospital, 16100 Genova, Italy
- Giuseppe Procopio
- Division of Oncology, IRCCS Foundation, Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy
- Elena Verzoni
- Division of Oncology, IRCCS Foundation, Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy
- Sergio Bracarda
- Division of Oncology, Santa Maria Hospital, 05100 Terni, Italy
- Martina Fanelli
- Division of Oncology, Department of Oncology, Hematology & Respiratory Diseases, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Roberto Sabbatini
- Division of Oncology, Department of Oncology, Hematology & Respiratory Diseases, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Rodolfo Passalacqua
- Division of Oncology, Hospital Trust of Cremona, 26100 Cremona, Italy
- Bruno Perrucci
- Division of Oncology, Hospital Trust of Cremona, 26100 Cremona, Italy
- Maria Olga Giganti
- Division of Oncology, Hospital Trust of Cremona, 26100 Cremona, Italy
- Maddalena Donini
- Division of Oncology, Hospital Trust of Cremona, 26100 Cremona, Italy
- Stefano Panni
- Division of Oncology, Hospital Trust of Cremona, 26100 Cremona, Italy
- Marcello Tucci
- Division of Oncology, Cardinal Massaia Hospital, 14100 Asti, Italy
- Veronica Prati
- Division of Oncology, Institute for Cancer Research and Treatment, Asl Cn2 Alba-Brà, 12042 Cuneo, Italy
- Cinzia Ortega
- Division of Oncology, Institute for Cancer Research and Treatment, Asl Cn2 Alba-Brà, 12042 Cuneo, Italy
- Anna Caliò
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
- Albino Eccher
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
- Filippo Alongi
- Advanced Radiation Oncology Department, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, 37024 Verona, Italy
- Giovanni Pappagallo
- Indipendent Researcher, Clinical Epidemiologist, Silea, 31057 Treviso, Italy
- Roberto Iacovelli
- Policlinico Universitario Fondazione Andrea Gemelli, 00168 Roma, Italy
- Alessandra Mosca
- Oncology, Candiolo Cancer Institute, IRCCS-FPO, 10060 Torino, Italy
- Paolo Umari
- Histopathology and Molecular Diagnostics, University Hospital Careggi, 50100 Firenze, Italy
- Ilaria Montagnani
- Histopathology and Molecular Diagnostics, University Hospital Careggi, 50100 Firenze, Italy
- Stefano Gobbo
- Department of Translation Medicine, Pathology Unit, University of Ferrara, 44100 Ferrara, Italy
- Francesco Atzori
- Oncology Unit, University and Hospital Trust of Cagliari, 09100 Cagliari, Italy
- Enrico Munari
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy
- Marco Maruzzo
- Oncology Unit, Oncology Department, Istituto Oncologico Veneto (IOV), IRCCS, 35128 Padua, Italy
- Umberto Basso
- Oncology Unit, Oncology Department, Istituto Oncologico Veneto (IOV), IRCCS, 35128 Padua, Italy
- Francesco Pierconti
- Division of Pathology, Policlinico Universitario Fondazione Agostino Gemelli, 00168 Roma, Italy
- Carlo Patriarca
- Pathology Unit, Department of Clinical Services, Sant’Anna Hospital, 22100 Como, Italy
- Piergiuseppe Colombo
- Department of Pathology, Department of Biomedical Sciences, Humanitas University, IRCCS Humanitas Clinical and Research Hospital, Pieve Emanuele, 20089 Milan, Italy
- Alberto Lapini
- Division of Urology, University Hospital Careggi, 50100 Firenze, Italy
- Giario Conti
- Division of Urology, Sant’Anna Hospital, 22100 Como, Italy
- Roberto Salvioni
- Department of Urology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy
- Enrico Bollito
- Department of Pathology, San Luigi Gonzaga Hospital, University of Turin, 10122 Torino, Italy
- Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena & Reggio Emilia, 41121 Modena, Italy
- Francesco Massari
- Medical Oncology, University and Hospital Trust of Bologna, 40138 Bologna, Italy
- Mimma Rizzo
- Division of Translational Oncology, IRCCS Istituti Clinici Scientifici ‘Maugeri’, 27100 Pavia, Italy
- Renato Franco
- Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Caserta, Italy
- Federica Zito-Marino
- Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Caserta, Italy
- Yoseba Aberasturi Plata
- Department of Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), 48900 Barakaldo, Spain
- Francesca Galuppini
- Department of Pathology, University and Hospital Trust of Padua, 35128 Padova, Italy
- Marta Sbaraglia
- Department of Pathology, University and Hospital Trust of Padua, 35128 Padova, Italy
- Matteo Fassan
- Department of Pathology, University and Hospital Trust of Padua, 35128 Padova, Italy
- Angelo Paolo Dei Tos
- Department of Pathology, University and Hospital Trust of Padua, 35128 Padova, Italy
- Maurizio Colecchia
- Department of Pathology, Uropathology Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele, 20132 Milano, Italy
- Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich, 8006 Zurich, Switzerland
- Maurizio Scaltriti
- AstraZeneca, New York, NY 10005, USA
- Camillo Porta
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, 70121 Bari, Italy
- Brett Delahunt
- Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, 3743 Wellington, New Zealand
- Gianluca Giannarini
- Urology Unit, “Santa Maria della Misericordia”, University of Udine, 33100 Udine, Italy
- Roberto Bortolus
- Department of Radiotherapy, CRO, 33081 Aviano, Italy
- Pasquale Rescigno
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Turin, Italy
- Giuseppe Luigi Banna
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Turin, Italy
- Alessio Signori
- Department of Health Sciences (DISSAL), Section of Biostatistics, University of Genova, 16100 Genova, Italy
- Miguel Angel Llaja Obispo
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16100 Genova, Italy
- Roberto Perris
- Department of Biosciences, COMT-Centre for Molecular and Translational Oncology, University of Parma, 43124 Parma, Italy
- Alessandro Antonelli
- Division of Urology, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University and Hospital Trust of Verona, 37134 Verona, Italy
- DOI
- https://doi.org/10.3390/jpm12050727
- Journal volume & issue
-
Vol. 12,
no. 5
p. 727
Abstract
We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3–G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.
Keywords
- clear cell renal cell carcinoma
- tumor sampling
- intratumoral heterogeneity
- angiogenesis
- immunity
- immunohistochemistry