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

ultimately leading to treatment failure. This dynamic process levels. Advanced radiological imaging modalities (e.g.,
contributes to the development of visible heterogeneity CT and MRI) have demonstrated some capability in
over time, which is referred to as temporal heterogeneity. visualizing tumor heterogeneity; however, these techniques
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In a study on neuroblastoma, the authors noted that PET/ require the integration of advanced software radionics
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CT-based diagnosis of intratumor heterogeneity in high- and AI. The transformative development of PET/CT
risk patients served as a strong prognostic indicator. This imaging has opened new avenues for investigating cancer
highlights the importance of serial advanced imaging characteristics and biology at the cellular and molecular
techniques in understanding temporal tumor evolution and levels. To date, F-FDG has been the most widely used
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predicting clinical outcomes. 8 radiotracer for staging, restaging, and monitoring therapy
response in different tumors. F-FDG has also been used
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Heterogeneity can manifest between different cells
within a single tumor (intra-tumor) or across different for prognostic assessments. Its role in diagnosing tumor
heterogeneity appears promising. In addition, the broad
patients harboring the same tumor type and can even
be observed when comparing primary tumors to their range of radiopharmaceuticals (tracers) utilized for PET/
metastases (inter-lesion). The diverse nature of tumor CT, coupled with whole-body imaging, has made PET
heterogeneity presents a significant challenge in cancer a potential option for non-invasively revealing tumor
management, highlighting the need for more sophisticated heterogeneity.
diagnostic and therapeutic approaches. 9 4. Tumor heterogeneity highlighted by

3. Challenges in diagnosing tumor various PET radiopharmaceuticals
heterogeneity In recent years, advances in PET/CT technology have
Diagnosing and precisely characterizing tumor transformed the field of oncology. With a deeper
heterogeneity can be highly challenging. Cancers and their understanding of the intricate TME, scientists have
developed an array of innovative PET tracers focusing on
molecular subtypes are typically identified using small improving cancer staging, restaging, and management.
biopsy samples taken from the primary site or a metastatic PET radiopharmaceuticals target a variety of mediators that
site. However, these biopsy samples are often limited localize in tumor cells and the cancer microenvironment
in size and may not fully represent the entire tumor’s through various mechanisms, providing different
heterogeneity. In addition, performing biopsies on all
metastatic sites involved in cancer is impractical. In a study information on cell biology and growth. The application
of these specialized PET tracers has allowed physicians
by one of the authors on medulloblastoma, high-grade and researchers to gain a more nuanced view of tumor
glioma, and renal cell carcinoma, it was demonstrated that, heterogeneity.
in terms of spatial heterogeneity, at least five biopsies are
required to detect 80% of somatic variants. 10 There are two potential methods for assessing tumor
heterogeneity using PET scans: (i) assessing heterogeneity
Similarly, other authors, like Savas et al., have in tracer distribution and quantifying metabolic parameters
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demonstrated the presence of spatial heterogeneity in F-FDG PET scans, and (ii) by utilizing multiple
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between primary tumors and their metastases in biopsy radiopharmaceuticals that target different characteristics
samples from breast cancer patients.
of tumor cells and microenvironment.
As biopsy samples are small and may not fully capture
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tumor type and heterogeneity, this approach may result in 5. F-FDG PET/CT: The workhorse of
inadequate treatment. This can lead to the administration oncological imaging
of one or more therapies that are not beneficial for a 18 F-FDG PET/CT remains the most widely used
given patient’s cancer, with potential harm/morbidity radiopharmaceutical for staging and response assessment
through lack of an effective drug regime. Heterogeneity of various malignancies. Increased glucose metabolism
also appears to be the primary cause of drug resistance. and uptake are observed in various cancer cells due to
While patients may initially react to a given therapy, new the upregulation of GLUT transporters and hexokinase
and resistant cancer cell clones regularly emerge within expression. F-FDG enters the cells through glucose
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the tumor, leading to disease progression or relapse. This transporters and is phosphorylated by hexokinase to
innate variability within tumors makes developing a one- produce F-FDG-6-phosphate, which remains trapped
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size-fits-all treatment approach exceedingly difficult. 12
in the cell and can be detected by PET scan. FDG
Medical imaging techniques possess the ability to uptake in tumor cells depends on tumor histopathology,
capture tumor characteristics at the cellular and molecular differentiation, aggressiveness, proliferative activity, and

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