3D fusion of histology to multi-parametric MRI for prostate cancer imaging evaluation and lesion-targeted treatment planning

Multi-parametric magnetic resonance imaging (mpMRI) of localized prostate cancer has the potential to support detection, staging and localization of tumors, as well as selection, delivery and monitoring of treatments. Delineating prostate cancer tumors on imaging could potentially further support the clinical workflow by enabling precise monitoring of tumor burden in active-surveillance patients, optimized targeting of image-guided biopsies, and targeted delivery of treatments to decrease morbidity and improve outcomes. Evaluating the performance of mpMRI for prostate cancer imaging and delineation ideally includes comparison to an accurately registered reference standard, such as prostatectomy histology, for the locations of tumor boundaries on mpMRI. There are key gaps in knowledge regarding how to accurately register histological reference standards to imaging, and consequently further gaps in knowledge regarding the suitability of mpMRI for tasks, such as tumor delineation, that require such reference standards for evaluation. To obtain an understanding of the magnitude of the mpMRI-histology registration problem, we quantified the position, orientation and deformation of whole-mount histology sections relative to the formalin-fixed tissue slices from which they were cut. We found that (1) modeling isotropic scaling accounted for the majority of the deformation with a further small but statistically significant improvement from modeling affine transformation, and (2) due to the depth (mean±standard deviation (SD) 1.1±0.4 mm) and orientation (mean±SD 1.5±0.9°) of the sectioning, the assumption that histology sections are cut from the front faces of tissue slices, common in previous approaches, introduced a mean error of 0.7 mm. To determine the potential consequences of seemingly small registration errors such as described above, we investigated the impact of registration accuracy on the statistical power of imaging validation studies using a co-registered spatial reference standard (e.g. histology images) by deriving novel statistical power formulae that incorporate registration error. We illustrated, through a case study modeled on a prostate cancer imaging trial at our centre, that submillimeter differences in registration error can have a substantial impact on the required sample sizes (and therefore also the study cost) for studies aiming to detect mpMRI signal differences due to 0.5 – 2.0 cm3 prostate tumors. With the aim of achieving highly accurate mpMRI-histology registrations without disrupting the clinical pathology workflow, we developed a three-stage method for accurately registering 2D whole-mount histology images to pre-prostatectomy mpMRI that allowed flexible placement of cuts during slicing for pathology and avoided the assumption that histology sections are cut from the front faces of tissue slices. The method comprised a 3D reconstruction of histology images, followed by 3D–3D ex vivo–in vivo and in vivo–in vivo image transformations. The 3D reconstruction method minimized fiducial registration error between cross-sections of non-disruptive histology- and ex-vivo-MRI-visible strand-shaped fiducials to reconstruct histology images into the coordinate system of an ex vivo MR image. We quantified the mean±standard deviation target registration error of the reconstruction to be 0.7±0.4 mm, based on the post-reconstruction misalignment of intrinsic landmark pairs. We also compared our fiducial-based reconstruction to an alternative reconstruction based on mutual-information-based registration, an established method for multi-modality registration. We found that the mean target registration error for the fiducial-based method (0.7 mm) was lower than that for the mutual-information-based method (1.2 mm), and that the mutual-information-based method was less robust to initialization error due to multiple sources of error, including the optimizer and the mutual information similarity metric. The second stage of the histology–mpMRI registration used interactively defined 3D–3D deformable thin-plate-spline transformations to align ex vivo to in vivo MR images to compensate for deformation due to endorectal MR coil positioning, surgical resection and formalin fixation. The third stage used interactively defined 3D–3D rigid or thin-plate-spline transformations to co-register in vivo mpMRI images to compensate for patient motion and image distortion. The combined mean registration error of the histology–mpMRI registration was quantified to be 2 mm using manually identified intrinsic landmark pairs. Our data set, comprising mpMRI, target volumes contoured by four observers and co-registered contoured and graded histology images, was used to quantify the positive predictive values and variability of observer scoring of lesions following the Prostate Imaging Reporting and Data System (PI-RADS) guidelines, the variability of target volume contouring, and appropriate expansion margins from target volumes to achieve coverage of histologically defined cancer. The analysis of lesion scoring showed that a PI-RADS overall cancer likelihood of 5, denoting “highly likely cancer”, had a positive predictive value of 85% for Gleason 7 cancer (and 93% for lesions with volumes \u3e0.5 cm3 measured on mpMRI) and that PI-RADS scores were positively correlated with histological grade (ρ=0.6). However, the analysis also showed interobserver differences in PI-RADS score of 0.6 to 1.2 (on a 5-point scale) and an agreement kappa value of only 0.30. The analysis of target volume contouring showed that target volume contours with suitable margins can achieve near-complete histological coverage for detected lesions, despite the presence of high interobserver spatial variability in target volumes. Prostate cancer imaging and delineation have the potential to support multiple stages in the management of localized prostate cancer. Targeted biopsy procedures with optimized targeting based on tumor delineation may help distinguish patients who need treatment from those who need active surveillance. Ongoing monitoring of tumor burden based on delineation in patients undergoing active surveillance may help identify those who need to progress to therapy early while the cancer is still curable. Preferentially targeting therapies at delineated target volumes may lower the morbidity associated with aggressive cancer treatment and improve outcomes in low-intermediate-risk patients. Measurements of the accuracy and variability of lesion scoring and target volume contouring on mpMRI will clarify its value in supporting these roles

Prostate Tumor Volume Measurement on Digital Histopathology and Magnetic Resonance Imaging

An accurate assessment of prostate tumour burden supports appropriate treatment selection, ranging from active surveillance through focal therapy, to radical whole-prostate therapies. For selected patients, knowledge of the three-dimensional locations and sizes of prostate tumours on pre-procedural imaging supports planning of effective focal therapies that preferentially target tumours, while sparing surrounding healthy tissue. In the post-prostatectomy context, pathologic measurement of tumour burden in the surgical specimen may be an independent prognostic factor determining the need for potentially life-saving adjuvant therapy. An accurate and repeatable method for tumour volume assessment based on histology sections taken from the surgical specimen would be supportive both to the clinical workflow in the post-prostatectomy setting and to imaging validation studies correlating tumour burden measurements on pre-prostatectomy imaging with reference standard histologic tumour volume measurements. Digital histopathology imaging is enabling a transition to a more objective quantification of some surgical pathology assessments, such as tumour volume, that are currently visually estimated by pathologists and subject to inter-observer variability. Histologic tumour volume measurement is challenged by the traditional 3–5 mm sparse spacing of images acquired from sections of radical prostatectomy specimens. Tumour volume estimates may benefit from a well-motivated approach to inter-slide tumour boundary interpolation that crosses these large gaps in a smooth fashion. This thesis describes a new level set-based shape interpolation method that reconstructs smooth 3D shapes based on arbitrary 2D tumour contours on digital histology slides. We measured the accuracy of this approach and used it as a reference standard against which to compare previous approaches in the literature that are simpler to implement in a clinical workflow, with the aim of determining a method for histologic tumour volume estimation that is both accurate and amenable to widespread implementation. We also measured the effect of decreasing inter-slide spacing on the repeatability of histologic tumour volume estimation. Furthermore, we used this histologic reference standard for tumour volume to measure the accuracy, inter-observer variability, and inter-sequence variability of prostate tumour volume estimation based on radiologists’ contouring of multi-parametric magnetic resonance imaging (MPMRI). Our key findings were that (1) simple approaches to histologic tumour volume estimation that are based on 2- or 3-dimensional linear tumour measurements are more accurate than those based on 1-dimensional measurements; (2) although tumour shapes produced by smooth through-slide interpolation are qualitatively substantially different from those obtained from a planimetric approach normally used as a reference standard for histologic tumour volume, the volumes obtained were similar; (3) decreasing inter-slide spacing increases repeatability of histologic tumour volume estimates, and this repeatability decreases rapidly for inter-slide spacing values greater than 5 mm; (4) on MPMRI, observers consistently overestimated tumour volume as compared to the histologic reference standard; and (5) inter-sequence variability in MPMRI-based tumour volume estimation exceeded inter-observer variability

Validation Strategies Supporting Clinical Integration of Prostate Segmentation Algorithms for Magnetic Resonance Imaging

Segmentation of the prostate in medical images is useful for prostate cancer diagnosis and therapy guidance. However, manual segmentation of the prostate is laborious and time-consuming, with inter-observer variability. The focus of this thesis was on accuracy, reproducibility and procedure time measurement for prostate segmentation on T2-weighted endorectal magnetic resonance imaging, and assessment of the potential of a computer-assisted segmentation technique to be translated to clinical practice for prostate cancer management. We collected an image data set from prostate cancer patients with manually-delineated prostate borders by one observer on all the images and by two other observers on a subset of images. We used a complementary set of error metrics to measure the different types of observed segmentation errors. We compared expert manual segmentation as well as semi-automatic and automatic segmentation approaches before and after manual editing by expert physicians. We recorded the time needed for user interaction to initialize the semi-automatic algorithm, algorithm execution, and manual editing as necessary. Comparing to manual segmentation, the measured errors for the algorithms compared favourably with observed differences between manual segmentations. The measured average editing times for the computer-assisted segmentation were lower than fully manual segmentation time, and the algorithms reduced the inter-observer variability as compared to manual segmentation. The accuracy of the computer-assisted approaches was near to or within the range of observed variability in manual segmentation. The recorded procedure time for prostate segmentation was reduced using computer-assisted segmentation followed by manual editing, compared to the time required for fully manual segmentation

The clinical application of PET/CT: a contemporary review

The combination of positron emission tomography (PET) scanners and x-ray computed tomography (CT) scanners into a single PET/CT scanner has resulted in vast improvements in the diagnosis of disease, particularly in the field of oncology. A decade on from the publication of the details of the first PET/CT scanner, we review the technology and applications of the modality. We examine the design aspects of combining two different imaging types into a single scanner, and the artefacts produced such as attenuation correction, motion and CT truncation artefacts. The article also provides a discussion and literature review of the applications of PET/CT to date, covering detection of tumours, radiotherapy treatment planning, patient management, and applications external to the field of oncology

Non-Cancerous Abnormalities That Could Mimic Prostate Cancer Like Signal in Multi-Parametric MRI Images

Prostate Cancer (PCa) is the most common non-cutaneous cancer in North American men. Multi-parametric magnatic resonance imaging (mpMRI) has the potential to be used as a non-invasive procedure to predict locations and prognosis of PCa. This study aims to examine non-cancerous pathology lesions and normal histology that could mimic cancer in mpMRI signals. This study includes 19 radical prostatectomy specimens from the London Health Science Centre (LHSC) that were marked with 10 strand-shaped fiducials per specimen which were used as landmarks in histology processing and ex vivo MRI. Initial registration between fiducials on histology and MR images was performed followed by the development of an interactive digital technique for deformable registration of in vivo to ex vivo MRI with digital histopathology images. The relationship between MRI signals and non-cancerous abnormalities that could mimic PCa has not been tested previously in correlation with digital histopathology imaging. The unregistered mp-MRI images are contoured by 4 individual radiology observers according to the Prostate Imaging Reporting and Data System (PI-RADS). Analysis of the radiology data showed prostatic intraepithelial neoplasia (PIN), atrophy and benign prostatic hyperplasia (BPH) as main non-cancerous abnormalities responsible for cancer like signals on mpMRI. This study will help increase the accuracy of detecting PCa and play a role in the diagnosis and classification of confounders that mimic cancer in MR images

Can CT scan protocols used for radiotherapy treatment planning be adjusted to optimise image quality and patient dose? A systematic review

This article reviews publications related to the use of CT scans for radiotherapy treatment planning, specifically the impact of scan protocol changes on CT number and treatment planning dosimetry and on CT image quality. A search on PubMed and EMBASE and a subsequent review of references yielded 53 relevant articles. CT scan parameters significantly affect image quality. Some will also affect Hounsfield unit (HU) values, though this is not comprehensively reported on. Changes in tube kilovoltage and, on some scanners, field of view and reconstruction algorithms have been found to produce notable HU changes. The degree of HU change which can be tolerated without changing planning dose by >1% depends on the body region and size, planning algorithms, treatment beam energy and type of plan. A change in soft-tissue HU value has a greater impact than changes in HU for bone and air. The use of anthropomorphic phantoms is recommended when assessing HU changes. There is limited published work on CT scan protocol optimization in radiotherapy. Publications suggest that HU tolerances of ±20 HU for soft tissue and of ±50 HU for the lung and bone would restrict dose changes in the treatment plan to <1%. Literature related to the use of CT images in radiotherapy planning has been reviewed to establish the acceptable level of HU change and the impact on image quality of scan protocol adjustment. Conclusions have been presented and further work identified

Computer-Assisted Characterization of Prostate Cancer on Magnetic Resonance Imaging

Prostate cancer (PCa) is one of the most prevalent cancers among men. Early diagnosis can improve survival and reduce treatment costs. Current inter-radiologist variability for detection of PCa is high. The use of multi-parametric magnetic resonance imaging (mpMRI) with machine learning algorithms has been investigated both for improving PCa detection and for PCa diagnosis. Widespread clinical implementation of computer-assisted PCa lesion characterization remains elusive; critically needed is a model that is validated against a histologic reference standard that is densely sampled in an unbiased fashion. We address this using our technique for highly accurate fusion of mpMRI with whole-mount digitized histology of the surgical specimen. In this thesis, we present models for characterization of malignant, benign and confounding tissue and aggressiveness of PCa. Further validation on a larger dataset could enable improved characterization performance, improving survival rates and enabling a more personalized treatment plan

Comparative Study With New Accuracy Metrics for Target Volume Contouring in PET Image Guided Radiation Therapy

[EN] The impact of positron emission tomography (PET) on radiation therapy is held back by poor methods of defining functional volumes of interest. Many new software tools are being proposed for contouring target volumes but the different approaches are not adequately compared and their accuracy is poorly evaluated due to the ill-definition of ground truth. This paper compares the largest cohort to date of established, emerging and proposed PET contouring methods, in terms of accuracy and variability. We emphasize spatial accuracy and present a new metric that addresses the lack of unique ground truth. Thirty methods are used at 13 different institutions to contour functional volumes of interest in clinical PET/CT and a custom-built PET phantom representing typical problems in image guided radiotherapy. Contouring methods are grouped according to algorithmic type, level of interactivity and how they exploit structural information in hybrid images. Experiments reveal benefits of high levels of user interaction, as well as simultaneous visualization of CT images and PET gradients to guide interactive procedures. Method-wise evaluation identifies the danger of over-automation and the value of prior knowledge built into an algorithm.For retrospective patient data and manual ground truth delineation, the authors wish to thank S. Suilamo, K. Lehtio, M. Mokka, and H. Minn at the Department of Oncology and Radiotherapy, Turku University Hospital, Finland. This study was funded by the Finnish Cancer Organisations.Shepherd, T.; Teräs, M.; Beichel, RR.; Boellaard, R.; Bruynooghe, M.; Dicken, V.; Gooding, MJ.... (2012). Comparative Study With New Accuracy Metrics for Target Volume Contouring in PET Image Guided Radiation Therapy. IEEE Transactions on Medical Imaging. 31(12):2006-2024. doi:10.1109/TMI.2012.2202322S20062024311

Multimodality Imaging in Prostate Cancer

ABSTRACT Prostate cancer is the most common cancer in men in Finland. Its aggressiveness varies widely, from indolent to fatal disease. Accurate characterization of prostate cancer is extremely essential to prevent overtreatment while sustaining good survivorship and high quality of life. This is feasible using novel technology in imaging and automatic tools in treatment planning. In the first part of this thesis work, the aim was to evaluate anti-1-amino-3-18Ffluorocyclobutane-1-carboxylic acid (18F-FACBC) PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer. The uptake of 18F-FACBC was significantly stronger in tumors with higher Gleason score and it may therefore assist in targeted biopsies when combined with MRI. 18F-FACBC PET/MRI outperformed PET/CT but did not demonstrate higher diagnostic performance than mpMRI performed separately. Furthermore, PET/MRI and mpMRI failed to detect pelvic lymph node metastasis measuring less than 8mm. 18F-FACBC PET/MRI is promising in characterization of primary prostate cancer, especially if ablative treatments are planned. It is not likely to replace mpMRI in clinical practice. The second study assessed multimodality imaging in detecting bone metastasis in high-risk prostate cancer and breast cancer patients. All patients underwent 99mTc-HDP bone scintigraphy (BS), 99mTc-HDP SPECT, 99mTc-HDP SPECT/CT, 18F-NaF PET/CT, and whole body (wb) MRI+DWI. 99mTc-HDP SPECT/CT, 18F-NaF PET/CT, and wbMRI+DWI had superior sensitivity compared to conventional nuclear imaging. In particular non-BS techniques showed less equivocal findings. wbMRI+DWI was as accurate as 18F-NaF PET/CT for detecting bone metastasis and may be considered a potential “single-step” imaging modality for detection of bone metastasis in high-risk patients with prostate and breast cancer. The purpose of the third study was to evaluate and validate the performance of a fully automated segmentation tool (AST) in MRI-based radiotherapy planning of prostate cancer. It showed high agreement for delineating prostate, bladder, and rectum, compared to manual contouring, and suggested adoption of AST in clinical practice. Finally, the fourth study investigated the long-term toxicity after biologically guided radiotherapy in men with localized prostate cancer. Carbon-11 acetate (11C-ACE) PET-CT was used to guide dose escalation into metabolically active intraprostatic lesions. 11C-ACE PET-guided radiotherapy was feasible and well tolerated. Although erectile dysfunction was relatively common, severe gastro-intestinal symptoms were very rare, and no grade 3 genitourinary symptoms were present at five years after radiotherapy. The findings of this thesis have potential to improve diagnostic imaging and radiotherapy planning in primary and metastatic prostate cancer. Eventually, they are likely to improve patients’ quality of life and survival. KEYWORDS: prostate cancer, magnetic resonance imaging, positron emission tomography, radiotherapy planning, toxicity, bone metastasisTIIVISTELMÄ Eturauhassyöpä on miesten yleisin syöpä Suomessa. Sen taudinkuva vaihtelee laajasti rauhallisesta aggressiiviseen ja tappavaan. On oleellista, että taudin luonne arvioidaan tarkasti, jotta vältytään sen liialliselta hoidolta, tinkimättä erinomaisista hoitotuloksista selviytymisessä ja elämän laadussa. Uudet kuvantamisteknologiat ja automaattityökalut mahdollistavat tämän. Tämän väitöskirjan ensimmäisessä osatyössä oli tavoitteena arvioida anti-1-amino-3-18Ffluorosyklobutaani-1-karboksyylihappo (18F-FACBC) PET-tietokonetomografiaa (TT), PET-magneettiresonanssikuvantamista (MRI) ja multiparametrista MRI-kuvantamista (mpMRI) eturauhassyövän diagnoosivaiheessa. 18F-FACBC-kertymät olivat tilastollisesti merkitsevästi voimakkaampia korkean Gleason-luokituksen kasvaimissa, joten yhdistettyä PET-MRI-kuvantamista voidaan käyttää hyväksi esimerkiksi kohdennetussa koepalojen otossa. 18F-FACBC PET-MRI oli parempi kuin PET-TT ja samanveroinen kuin mpMRI eturauhassyövän diagnostiikassa. PET-MRI ja mpMRI eivät havainneet alle 8 mm:n läpimittaisia imusolmukemetastaaseja. 18F-FACBC PET-MRI on lupaava kuvantamismuoto eturauhassyövän diagnostiikassa, erityisesti kajoavia hoitoja suunniteltaessa, mutta ei korvanne mpMRI:a kliinisessä käytössä. Toinen osatyö käsitteli luustoetäpesäkkeiden toteamista eri kuvantamismenetelmillä korkean uusiutumisriskin eturauhas- ja rintasyöpäpotilailla. Kaikille potilaille tehtiin 99mTc-HDP luustokarttakuvaus, 99mTc-HDP SPECT, 99mTc-HDP SPECT-TT, 18F-NaF PET-TT ja koko kehon MRI diffuusiopainotettuna (wbMRI+DWI). 99mTc-HDP SPECT-TT, 18F-NaF PET-TT ja wbMRI+DWI olivat perinteistä luustokarttaa herkempiä luustometastaasien toteamisessa, koska epäspesifeiksi määriteltyjä muutoksia oli vähemmän. wbMRI+DWI osoitti yhtäläistä tarkkuutta luustometastaasien diagnosoinnissa 18F-NaF PET-TT:n verrattuna, joten sitä voitaisiin hyödyntää, käytettäessä vain yhtä kuvantamistapaa näiden potilaiden luustometastaasien toteamiseen. Kolmas osatyö arvioi ja validoi täysin automaattisen piirtotyökalun käyttöä MRI-pohjaisen sädehoidon suunnittelussa eturauhassyöpäpotilailla. Työkalu suoriutui hyvin eturauhasen, virtsarakon ja peräsuolen rajauksesta asiantuntijan käsin tekemiin rajauksiin verrattuna, puoltaen työkalun käyttöä luotettavasti myös kliinisessä työssä. Viimeisenä, neljännessä osatyössä arvioitiin biologisesti ohjatun eturauhassyövän sädehoidon aiheuttamia pitkäaikaishaittoja. Hiili-11 asetaatti (11C-ACE) PET-TT-kuvantamisen avulla suunniteltiin sädehoito, jossa metabolisesti aktiivisiin eturauhasen sisäisiin muutoksiin kohdistettiin korkeammat sädeannokset. 11C-ACE-PET-TT-ohjattu sädehoito oli toteuttamiskelpoinen ja hyvin siedetty. Vaikka erektiohäiriöt olivat suhteellisen yleisiä, vakavat suoliston haittavaikutukset olivat hyvin harvinaisia, eikä kolmannen asteen virtsateiden haittavaikutuksia esiintynyt lainkaan viiden vuoden kuluttua sädehoidosta. Tämän väitöskirjan löydökset voivat parantaa eturauhassyövän primaaridiagnostiikan kuvantamista ja sädehoidon suunnittelua, sekä luustoetäpesäkkeiden diagnostiikkaa. Näin voidaan kohentaa potilaiden elämänlaatua ja selviytymistä. AVAINSANAT: Eturauhassyöpä, magneettikuvaus, positroniemissiotomografia, sädehoidon suunnittelu, haittavaikutukset, luuston etäpesäkkee