Standardizing the pathologic assessment of HER2-(ultra)low breast cancer - insights from a national Italian project

Sep 23, 2026

Novel therapies for HER2-(ultra)low breast cancer have shifted HER2 status from a simple binary system to a multi-tier framework defined by immunohistochemistry (IHC). Pre-analytical and analytical variables can affect accurate identification of HER2 expression at the lowest IHC range. A national Italian project evaluated diagnostic challenges and classification practices through surveys, whole-slide image scoring, and on-site discussions, then compared results with an expert panel. Agreement was substantial overall but decreased in the most challenging ultralow spectrum cases.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Summary

Objective

Material and methods

Results

Conclusions

PATHOLOGICA 2025;117:559-570 DOI: 10.32074/1591-951X-1565 Received: July 31, 2025 Accepted: October 28, 2025 Correspondence Cristian Scatena E-mail: [cristian.scatena@unipi.it](cristian.scatena@unipi.it)[ ](cristian.scatena@unipi.it)Isabella Castellano E-mail: isabella.castellano@unito. it How to cite this article: Cerbelli B, Marletta S, Amato M, et al. Standardizing the pathologic assessment of HER2-(ultra)low breast cancer: insights from a national Italian project. Pathologica 2025;117:559-570 . [https://doi](https://doi). org/10.32074/1591-951X-1565 © Copyright by Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology OPEN ACCESS This is an open access journal distributed in accordance with the CC-BY-NC-ND (Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International) license: the work can be used by mentioning the author and the license, but only for non-commercial purposes and only in the original version. For further information: [https://creativecommons](https://creativecommons). org/licenses/by-nc-nd/4.0/deed.en Original article Standardizing the pathologic assessment of HER2-(ultra)low breast cancer: insights from a national Italian project Bruna Cerbelli\#, Stefano Marletta2,3\#, Michelina Amato4 , Michela Campora5 , Leopoldo Costarelli 4 , Antonio Cossu6 , Veronica Errigo7 , Gerardo Ferrara8 , Maria Pia Foschini9 , Renato Franco10 , Nicola Fusco11 , Antonio Marchetti12 , Mauro G Mastropasqua13 , Enrico Orvieto14 , Francesca Pietribiasi15 , Moira Ragazzi16 , Antonio Rizzo17 , Alfredo Santinelli18 , Fabrizio Zanconati19 , Giulia d’Amati1 , Cristian Scatena20 , Isabella Castellano21 and GIPaM working group 1 Department of Radiology, Oncology and Pathology, Sapienza, University of Rome, Rome, Italy; 2 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy; 3 Division of Pathology, Humanitas Istituto Clinico Catanese, Catania, Italy; 4 Department of Pathology, San Giovanni-Addolorata Hospital, Rome Italy; 5 Department of Pathology, Santa Chiara Hospital, APSS Trento, Trento, Italy; 6 Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 7 Anatomical Pathology Unit, Ospedale San Paolo, Savona, Italy; 8 Pathological Anatomy and Cytopathology Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 9 Department of Biomedical and Neuromotor Sciences, University of Bologna, Anatomic Pathology at Bellaria Hospital, Bologna, Italy; 10 Department of Mental and Physical Health and Preventive Medicine, Pathology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy; 11 Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Oncology and HematoOncology, University of Milan, Milan, Italy; 12 Department of Medical, Oral and Biotechnological Sciences, Centre for Advanced Studies and Technology (CAST), University of Chieti, Chieti, Italy; 13 Department of Precision a14ndDeRegparteneramenttvfePMeathilcoinegy, and JULSSon8ianBerAicrea,aS, ScanhoBoorltoolMHicpiinetal,, UVincversnza,ityItaolfy;B1a5riDi“AvidioonMoroof Pa”t,hBaroloig,Iy,taly; Santa Croce Hospital, Moncalieri, Turin, Italy; 16 Pathology Unit, Arcispedale Santa Maria Nuova, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy; 17 Division of Pathology, Clinical Institute Humanitas Catania Cubba, Misterbianco (Catania), Italy; 18 Anatomic Pathology, Azienda Sanitaria Territorialedi Pesaro-Urbino, Pesaro, Italy; 19 Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy; 20 Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 21 Department of Medical Science, University of Turin, Turin, Italy \#these authors are equally contributed Summary Objective. Novel therapies for HER2-(

FAQs

Why was standardization needed for HER2-(ultra)low breast cancer assessment?

Because multi-tier HER2 classification based on IHC introduces sensitivity to pre-analytical and analytical factors, making accurate identification at the lowest expression range challenging.

How was the national Italian project conducted?

A total of 121 pathologists completed an online survey, scored eight HER2-(ultra)low IHC whole-slide images, and joined on-site meetings to discuss results and evaluate additional challenging WSIs.

What were the main findings on agreement with the expert panel?

Overall agreement was substantial (69%), with higher agreement in the online phase than the on-site phase. Discordances were most common in the on-site cohort and within the HER2 0+/ultralow spectrum.

What does the study conclude about clinical practice?

Accurate classification of HER2-(ultra)low breast cancers remains complex, and variability in difficult cases supports the need for standardized assessment procedures.

Sep 23, 2026

Uploaded by MrHarris58