Introducing higher harmonic generation microscopy for renal tumour pathology: a perspective on clinical translation.
6 affiliations
- 1Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
- 2Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam, The Netherlands.
- 3LaserLab Amsterdam, Department of Physics, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- 4Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
- 5Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
- 6Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
Higher harmonic generation microscopy (HHGM) is an emerging nonlinear optical imaging modality that combines second harmonic generation (SHG), third harmonic generation (THG), and two-photon excited autofluorescence (2PEF) to generate high-resolution, label-free images of fresh biological tissue. By exploiting intrinsic optical contrast arising from nonlinear light-tissue interactions, HHGM enables rapid visualisation of cellular morphology, extracellular matrix architecture, and the tumour microenvironment without fixation or staining. These unique biophysical properties have facilitated the clinical translation of HHGM for real-time tissue assessment across several oncological applications. Renal tumour pathology represents a promising yet underexplored application of HHGM, particularly because rapid assessment of biopsy adequacy and tumour representativeness remains an important unmet clinical need. In this perspective, we discuss the biophysical principles of HHGM, review the current evidence supporting its application in oncological pathology, and present representative images that illustrate the characteristic multimodal appearance of renal cell carcinoma (RCC) and normal renal parenchyma, highlighting qualitative correspondence with conventional haematoxylin and eosin histology. In addition, HHGM enables visualisation of stromal architecture and the tumour microenvironment in fresh, unprocessed tissue within minutes. Although the ongoing prospective Intelligence Imaging (INTIMA) study is designed to validate the diagnostic accuracy, reproducibility, and clinical utility of HHGM in renal tumour pathology, these findings should be considered preliminary until such validation is completed. If confirmed, together with continued advances in nonlinear optical microscopy, digital pathology, and artificial intelligence (AI), HHGM could become a valuable adjunct to routine histopathological assessment and real-time biopsy evaluation.
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BibTeX
@article{duijn2026introducing,
title = {{Introducing higher harmonic generation microscopy for renal tumour pathology: a perspective on clinical translation.}},
author = {M Duijn and S Spies and L T de Haan and D M de Bruin and M M Lange and C D Savci and O M van Delden and M L Groot and P J Zondervan},
journal = {Biophysical reviews},
year = {2026},
month = aug,
doi = {10.1007/s12551-026-01453-8},
url = {https://europepmc.org/article/MED/42927108},
note = {CC BY},
}
RIS
TY - JOUR
TI - Introducing higher harmonic generation microscopy for renal tumour pathology: a perspective on clinical translation.
AU - M Duijn
AU - S Spies
AU - L T de Haan
AU - D M de Bruin
AU - M M Lange
AU - C D Savci
AU - O M van Delden
AU - M L Groot
AU - P J Zondervan
PY - 2026
DA - 2026/08/01
JO - Biophysical reviews
DO - 10.1007/s12551-026-01453-8
UR - https://europepmc.org/article/MED/42927108
AB - Higher harmonic generation microscopy (HHGM) is an emerging nonlinear optical imaging modality that combines second harmonic generation (SHG), third harmonic generation (THG), and two-photon excited autofluorescence (2PEF) to generate high-resolution, label-free images of fresh biological tissue. By exploiting intrinsic optical contrast arising from nonlinear light-tissue interactions, HHGM enables rapid visualisation of cellular morphology, extracellular matrix architecture, and the tumour microenvironment without fixation or staining. These unique biophysical properties have facilitated the clinical translation of HHGM for real-time tissue assessment across several oncological applications. Renal tumour pathology represents a promising yet underexplored application of HHGM, particularly because rapid assessment of biopsy adequacy and tumour representativeness remains an important unmet clinical need. In this perspective, we discuss the biophysical principles of HHGM, review the current evidence supporting its application in oncological pathology, and present representative images that illustrate the characteristic multimodal appearance of renal cell carcinoma (RCC) and normal renal parenchyma, highlighting qualitative correspondence with conventional haematoxylin and eosin histology. In addition, HHGM enables visualisation of stromal architecture and the tumour microenvironment in fresh, unprocessed tissue within minutes. Although the ongoing prospective Intelligence Imaging (INTIMA) study is designed to validate the diagnostic accuracy, reproducibility, and clinical utility of HHGM in renal tumour pathology, these findings should be considered preliminary until such validation is completed. If confirmed, together with continued advances in nonlinear optical microscopy, digital pathology, and artificial intelligence (AI), HHGM could become a valuable adjunct to routine histopathological assessment and real-time biopsy evaluation.
SN - 1867-2450
SN - 1867-2469
ER -