Page 10 - ARNM-3-2

Advances in Radiotherapy
& Nuclear Medicine Role of PET/CT in exploring tumor heterogeneity

traditional treatment methods (e.g., chemotherapy and Within the TME, stromal components secrete growth
radiotherapy) to more personalized (precise) medicine factors and angiogenic factors (e.g., transforming growth
– incorporating targeted drugs and individualized factor β1, vascular endothelial growth factor, interleukin
treatments based on each patient’s unique genes, 6, and tumor necrosis alpha [TNF-α]). This dynamic
environment, and lifestyle – assessing tumor heterogeneity environment provides nutritional and mechanical
becomes increasingly important. In recent years, several support that enhances cancer metabolism, promoting
anticancer drugs have been approved and specifically tumor growth through local invasion and resistance to
developed to target the unique morphological, molecular, cell death signals. The characteristics of the TME vary
and genetic characteristics of cancer cells. Accurate greatly between tumor types – it can be fibrotic, rich in
diagnosis and quantification of tumor heterogeneity is blood vessels, or even necrotic. Tumor cells also exhibit
crucial to predict disease progression, as heterogeneity various phenotypic characteristics, such as cell surface
3
can be highly variable even within a single individual. receptors, rate of antigenicity, metabolic activity, hormone
Diagnosing tumor heterogeneity is quite challenging, and receptor status, and indicators of tumor aggressiveness or
the role of pathology, radiological imaging, radiomics, and metastatic potential. These characteristics provide crucial
artificial intelligence (AI) has been described in various insights into the behavior and biology of tumors, aiding
4
literature. Radiological images, including ultrasound, in diagnosis, prognosis, and the development of targeted
computed tomography (CT), and magnetic resonance therapies. In addition, various factors, such as genetic
imaging (MRI), can identify heterogeneity to a certain mutations, cellular heterogeneity, and microenvironment
extent by texture analysis and the shape and volume of interactions, also play significant roles in determining
5
lesions. However, radiological imaging requires special tumor behavior and treatment response. As tumors
software and expertise and cannot provide comprehensive transition from primary to invasive disease, the tumor and
information on total body lesions in a single scan, as its microenvironment evolve, resulting in the spatial and
positron emission tomography/CT (PET/CT) can. This temporal emergence of tumor heterogeneity. 2,3
review delves into various aspects of PET/CT in describing Spatial heterogeneity refers to the variation in tumor
heterogeneity and its impact on clinical management. characteristics, such as cell morphology and genetic
Radiomics and AI techniques are further enhancing our makeup, within the primary tumor or between its metastases
understanding of tumor complexity. This short review also at a single time point. Conversely, temporal heterogeneity
describes the role of different PET radiopharmaceuticals describes changes in these tumor characteristics that
(tracers) in imaging various characteristics of tumor tissue develop over time as the disease progresses. Both forms of
that contribute to heterogeneity in various cancers. heterogeneity play a critical role in understanding tumor
behavior, treatment resistance, and disease evolution.
4
2. Tumor heterogeneity: Concepts and Detection and quantification of spatial and temporal
mechanisms tumor heterogeneity can provide critical insights for cancer
5
Cancer and its metastases arise from a process of treatment. Jonsson et al. studied spatial heterogeneity on
uncontrolled and unchecked cell proliferation, which PET/CT scans in three types of cancers using an image
invades healthy tissues and spreads throughout the registration-based framework. Their findings demonstrated
body. Tumor clonality represents a key characteristic of that spatial tumor heterogeneity can be effectively detected
malignancy and is defined as the expansion of transformed and quantified based on lesion frequency, volume, and
cells derived from a founding cell that initially acquired metabolic activity. This approach highlights the potential of
deregulated growth capability. In contrast, cancer advanced imaging techniques to better understand tumor
5
development is a multi-step process in which cells undergo behavior and guide personalized treatment strategies.
6
several genetic or environmental alterations, transforming Hughes et al., in their study on lung cancer using PET/
CT scans, demonstrated that quantification of spatial
into cell types different from their original progenitor cells fluorodeoxyglucose (FDG) uptake heterogeneity provides
and contributing to heterogeneity. 1
prognostic value beyond standardized uptake value (SUV)
Solid cancer lesions consist of tumor cells and the and the clinical stage of cancer. Various studies have
tumor microenvironment (TME). The TME is made demonstrated that tumors and their metastases consist
of cells and extracellular components (blood and of different clones of cells, each with distinct genetic,
lymphatic vessels, cytokines, mediators, etc.). The cellular epigenetic, proteomic, and transcriptomic profiles, yet
components included in this complex are tumor cells, descending from a common ancestor. These diverse clones
immune cells, and stromal cells (fibroblasts, mesenchymal may exhibit varying responses to treatment, with some
stem cells, adipocytes, endothelial cells, and pericytes). clones resisting therapy and continuing to proliferate,

Volume 3 Issue 2 (2025) 2 doi: 10.36922/ARNM025040005