Correlation of histopathology and multi-modal magnetic resonance imaging in childhood osteosarcoma: Predicting tumor response to chemotherapy

Abstract

Background Osteosarcoma, which is the most common malignant pediatric bone cancer, remains dependent on an imprecise systemic treatment largely unchanged in 30 years. In this study, we correlated histopathology with magnetic resonance imaging (MRI), used the correlation to extract MRI-specific features representative of tumor necrosis, and subsequently developed a novel classification model for predicting tumor response to neoadjuvant chemotherapy in pediatric patients with osteosarcoma using multi-modal MRI. The model could ultimately serve as a testable biomarker for a high-risk malignancy without successful precision treatments. Methods Patients with newly diagnosed high-grade appendicular osteosarcoma were enrolled in a single-center observational study, wherein patients underwent pre-surgical evaluation using both conventional MRI (post-contrast T1-weighted with fat saturation, pre-contrast T1-weighted, and short inversion-time inversion recovery (STIR)) and advanced MRI (diffusion weighted (DW) and dynamic contrast enhanced (DCE)). A classification model was established based on a direct correlation between histopathology and MRI, which was achieved through histologic-MR image co-registration and subsequent extraction of MR image features for identifying histologic tumor necrosis. By operating on the MR image features, tumor necrosis was estimated from different combinations of MR images using a multi-feature fuzzy clustering technique together with a weighted majority ruling. Tumor necrosis calculated from MR images, for either an MRI plane of interest or whole tumor volume, was compared to pathologist-estimated necrosis and necrosis quantified from digitized histologic section images using a previously described deep learning classification method. Results 15 patients were enrolled, of whom two withdrew, one became ineligible, and two were subjected to inadequate pre-surgical imaging. MRI sequences of n = 10 patients were subsequently used for classification model development. Different MR image features, depending on the modality of MRI, were shown to be significant in distinguishing necrosis from viable tumor. The scales at which MR image features optimally signified tumor necrosis were different as well depending on the MR image type. Conventional MRI was shown capable of differentiating necrosis from viable tumor with an accuracy averaging above 90%. Conventional MRI was equally effective as DWI in distinguishing necrotic from viable tumor regions. The accuracy of tumor necrosis prediction by conventional MRI improved to above 95% when DCE-MRI was added into consideration. Volume-based tumor necrosis estimations tended to be lower than those evaluated on an MRI plane of interest. Conclusions The study has shown a proof-of-principle model for interpreting chemotherapeutic response using multi-modal MRI for patients with high-grade osteosarcoma. The model will continue to be evaluated as MR image features indicative of tumor response are now computable for the disease prior to surgery.

Principles of orthopedic treatment for malignant bone tumors in children

“…Good reaction is stated when necrosis constitutes over 90% of resected tumor in osteosarcoma cases and 100% for Ewing sarcoma [17]. Recently, new imaging tools were investigated to make the MRI based accuracy of tumor necrosis assessment more reliable, and to allow more precise planning of the surgical margins [18].…”

Characteristic of Apparent Diffusion Coefficient and Time Intensity Curve Analysis of Dynamic Contrast Enhanced MRI in Osteosarcoma Histopathologic Subtypes

“…Prognostic and treatment response of osteosarcoma patient's evaluation are also the important aspects. Thus, the combination of advanced MRI techniques and conventional MRI is needed to increase the accuracy of diagnostic 5 , 6 , 7 , 8 , 9 . Advanced MR imaging techniques enable the assessment of treatment-related response with the use of the presurgical study.…”

“…Moreover, the comprehensive analysis of anatomical and functional MR imaging sequences, compared with histopathologic examination, is a non-invasive and easily integrated with a routine presurgical examination. DCE MR imaging has also been studied for the assessment of treatment response in the patients with musculoskeletal tumors, but mainly in osteosarcomas 5 , 7 , 8 , 9 , 11 .…”

“…ADC values from advanced MRI study could differentiate osteosarcoma with its differential diagnosis from other bone tumors e.g. Ewing's sarcoma 7 , 9 , 12 . On the other hand, in the study by Yakushiji et al, it was difficult to distinguish osteosarcomas from chondrosarcomas, those tumors showed a restricted diffusion in DWI, while ADC value was considerably low.…”

“…On the other hand, in the study by Yakushiji et al, it was difficult to distinguish osteosarcomas from chondrosarcomas, those tumors showed a restricted diffusion in DWI, while ADC value was considerably low. Thus, the use of water diffusion was embedded as a surrogate marker to characterize a highly cellular regions of tumor versus acellular and necrotic regions 6 , 7 , 8 , 9 , 12 . The increased diagnostic accuracy may possible if DWI is used in conjunction with morphological gadolinium enhanced on MRI 12 .…”