Nuclear medicine imaging modalities to detect incidentalomas and their impact on patient management: a systematic review

Purpose This systematic review aims to investigate the role of nuclear imaging techniques in detecting incidentalomas and their impact on patient management. Methods Following PRISMA guidelines, a comprehensive literature search was conducted from February to May 2022. Studies in English involving patients undergoing nuclear medicine studies with incidental tumor findings were included. Data on imaging modalities, incidentaloma characteristics, management changes, and follow-up were extracted and analyzed. Results Ninety-two studies involving 64.884 patients were included. Incidentalomas were detected in 611 cases (0.9%), with thyroid being the most common site. PET/CT with FDG and choline tracers showed the highest incidentaloma detection rates. Detection of incidentalomas led to a change in therapeutic strategy in 59% of cases. Various radiotracers demonstrated high sensitivity for incidentaloma detection, particularly in neuroendocrine tumors and prostate cancer. Conclusion Nuclear imaging techniques play a crucial role in detecting incidentalomas, leading to significant changes in patient management. The high sensitivity of these modalities highlights their potential in routine oncology follow-up protocols. Future directions may include enhancing spatial resolution and promoting theranostic approaches for improved patient care. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-024-05891-3.


Introduction
In the twenty-first century, cancer is still considered the second most frequent cause of death after cardiovascular diseases.Through the years, screening methods were increasingly implemented to decrease the mortality rate and to hasten therapeutic strategies.Despite the wide use of CT and MRI imaging, nuclear medicine imaging, indeed, has gained more importance, playing a pivotal role in the diagnostic Roberta Costanzo and Gianluca Scalia have contributed equally to the manuscript and share first authorship.
Sebastiano Cosentino and Giuseppe E. Umana contributed equally to the manuscript and share senior authorship.
process and treatment, especially thanks to the use of different radiotracers that can easily detect different malignancies.(Panareo et al. 2021) Indeed, the term "incidentaloma" was introduced to describe the detection of a lesion by chance (either malignant or benignant) while performing an exam for another clinical indication, even leading to the coining of the term "positron emission tomography (PET)-associated incidental neoplasm" (PAIN) by Katz and Shaha. (Katz and Shaha 2008).
Nuclear medicine imaging techniques, using various radiotracers for different indications, can detect many incidental findings located in different parts of the body.The length of axial field of view (FOV), indeed, may influence scanner sensitivity, requiring a longer FOV to detect images in lesser time and to cover a wider body surface with a lower dose.Thanks to these characteristics, many incidentaloma might be easily detected using these techniques.(Alberts et al. 2023) The most common are in the thyroid, in the gastrointestinal tract, lungs and, in extremely rare cases, in breast.Clearly, an incidental finding can completely change the therapeutic strategies and the approach to the patient and its condition.(Panareo et al. 2021).
Hence, the aim of this systematic review is to investigate and discuss the role of nuclear imaging techniques, their relationship with incidentaloma detection, the advances, and the limitations currently related, and the consequent impact on patient management.

Search strategy
An accurate search of the current literature was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (Fig. 1) statement, with no limits in terms of publication date.
The role of the current review was to analyze different nuclear medicine imaging techniques used to detect incidental lesions, and to evaluate their impact on patient management.

Eligibility criteria
The following inclusion criteria were applied: studies in the English language, studies involving patients undergoing nuclear medicine studies with incidental findings of primary tumors, age > 18, and presence of clinical data.We deemed eligible for inclusion in this review case reports, cohort prospective and retrospective studies, and clinical trials.
Articles were excluded if they did not deal with clinical management of patients, patients < 18 years old, no detection of incidental tumors, and no English language.

Selection process
The search was performed from February 2022 to May 2022.The initial search was conducted by four independent authors (FP, RC, LB and AS) using the previously reported keywords.Records were summarized into a single Excel file.All the duplicates were removed.Each author independently screened the titles, abstracts, and full manuscripts using the previously reported selective criteria.Then, the results were analyzed and combined.Another author (GS) also performed a further manual search to identify additional studies of the reference sections of the selected papers.

Study characteristics
A total of 92 studies were involved in statistical analysis.Regarding the study design, most were case reports (72/92).The remaining studies were 4 case series, 14 retrospective studies, 2 prospective studies and 1 population study.A total of 64,884 patients were involved.611 incidentalomas were detected (0.9%).(Suppl.1).
Of the incidentalomas detected, 611 were primitive lesions and the most common site was the thyroid.
In 10 (11%) studies, nuclear medicine imaging was performed before surgery instead of 20 after surgery.In 10 (11%) studies, patients did not perform surgery, and 55 (60%) studies did not report the data.(Table 2).
The mean SUV at baseline of the incidentalomas in the different studies was 6.6, ranging from 2.4 to 41.4, in the overall population.We also analyzed the SUV measurements across various nuclear medicine imaging modalities.For 18F choline PET/CT, SUV values ranged from 3.1 to 12, with notable averages of 9.6 and 4.5 for malignant lesions.In contrast, benign lesions showed lower SUV values.Similarly, 18F choline PET showed SUV values ranging from 2.4 to 11 across different studies.11C choline PET reported an SUV of 6.0.68 Ga PSMA-PET/CT results varied widely, with SUV values between 3.1 and 24.5.Whole-body FDG-PET/CT showed significant variations, with SUV values

Discussion
PET in oncological diagnosis is gaining a pivotal role, transforming PET, PET/CT, and scintigraphy into essential imaging tools for detecting and staging malignant lesions.Various radiotracers, linked to different pathophysiological pathways, can identify changes in cellular metabolism, thereby detecting neoplastic tissue.These radiopharmaceutical isotopes are highly specific and absorbed by neoplastic hypermetabolic cells.PET or PET/CT and scintigraphy are primarily used for diagnosis and tumor staging, and an incidental finding, such as a second malignant lesion, can significantly alter medical strategies and patient management (Katz and Shaha 2008;Alberts et al. 2023).
This is an interesting issue we would like to address in this systematic review.This review revealed which nuclear imaging techniques can detect the higher rate of incidentalomas and the implication of this casual discovery to determine the best therapeutic strategies for patients' care.
Literature data show that the most common incidental findings are in the thyroid, gastrointestinal tract, and lungs, with an incidence ranging from 1% to 3%, with a clear prevalence for thyroid incidentalomas.According to our literature review, the most represented imaging technique capable of detecting an incidentaloma is PET/CT with the following radiotracers: 18F-fluoro-2-deoxy-D-glucose (FDG) and 18F-choline.The total number of incidentalomas reported here (611) may appear to be exiguous, accounting for 0.9%, but we believe this data is underestimated and deserves further interpretation.
First, the use of PET/CT is limited due to its costs, device availability, and lack of protocols supporting its mandatory use.Second, the increasing use of modern radiosurgical and stereotactic radiotherapy techniques, such as gamma knife, cyberknife, and proton beam, both with single fraction or hypofractionated regimes, requires routine use of nuclear medicine imaging modalities to detect the clonogenic microscopic infiltration of the tumor that is not visible with standard imaging.This microscopic infiltration affects the feasibility of the treatment, as reported in our previous studies (Albano et al. 2022;Inserra et al. 2022;Barone et al. 2021).Radiosurgical treatments may not be suitable if PET/CT shows extensive bony infiltration, not visible on MRI scans.Similarly, the detection of multiple lesions not documented on MRI changes the SRS plan and dose delivery (Albano et al. 2022).Since the use of SRS treatments is increasing and with this the related nuclear medicine investigation, we can assume that the number of incidentalomas reported may rise in the near future.
In this literature review emerged that the detection of incidentalomas lead to a change in the therapeutic strategy in hundreds of patients, accounting for 59% of incidentaloma.Also, this undoubtful consistent data may be even underestimated, since a large number of papers didn't report detailed information on the management of 179 new discovered lesions (29%).
Of notice, most of the tracers reported appear to be highly sensitive for incidentalomas detection.Of 47 patients that performed 131I-NP-59 PET scan, all 47 showed incidentalomas.(Cava et al. 2003) The same for all 17 68Ga PSMA-PET/CT that showed 17 incidentalomas patients, and 67Ga Scintigraphy, 99mTc-colloid.(Sasikumar et al. 2017;Ciappuccini et al. 2019;Demirkol et al. 2017;Punch et al. 2006;Hirano et al. 1993) Similarly, all the other tracers demonstrated the capability to detect new lesions and in particular FDG-PET showed a significant rate of incidentalomas detection, especially if considered that this investigation is widely used in oncology for several histotypes.Despite FDG-PET documented a low incidence of new lesions, its diffuse application led to a high number of incidentalomas.
68Ga-DOTATATE and DOTATOC showed a relatively lower number of incidentalomas, (Chan and Hsiao 2016;Cleary et al. 2016;Albano et al. 2022) but it should be considered that these investigations are used only in selected cases, mainly in the assessment of meningiomas and neuroendocrine tumors and in particular for Gamma knife (GK) planning.Thus, the reported 4% of new lesions is not negligible especially considering that not all GK center perform 68Ga-DOTATATE or DOTATOC scans due to lack of clear protocols and of tracer availability.
Another question that deserves to be mentioned are the new application of tracers for histology other than the usual, like 68Ga PSMA-PET/CT that is commonly used in prostate cancer but that has been reported to be beneficial in radiotherapy contouring of patients affected by gliomas due its highly sensitivity for the detection of glioblastoma infiltration (Şahin et al. 2022).68Ga PSMA-PET/CT is able to highlight glioma infiltration not visible with standard imaging, similarly to 68Ga-DOTATATE or DOTATOC that can detect the clonogenic infiltration, and thus allowing for a more precise definition of tumoral edges crucial during radiotherapy contouring.(Umana et al. 2022) The analysis of SUV values across various nuclear medicine imaging modalities reveals significant variability, underscoring the importance of interpreting these values within the context of each specific modality.For instance, 18F choline PET/CT showed SUV values ranging from 3.1 to 12, with higher values typically indicating malignant lesions.In contrast, benign lesions had lower SUV values.Similarly, 68Ga PSMA-PET/CT displayed a wide range of SUVs from 3.1 to 24.5, demonstrating its sensitivity in detecting various incidentalomas, including glioma infiltrations.Whole-body FDG-PET/CT exhibited even greater variability, with SUVs reaching up to 41.4, reflecting the hypermetabolic activity common in many malignancies.These differences highlight the necessity for modalityspecific interpretation of SUV measurements, as accurate assessment is crucial for identifying incidentalomas and making informed changes in therapeutic strategies.This tailored approach ensures that incidental findings are effectively characterized, leading to better patient management and outcomes.

History of PET
Positron emission tomography is an imaging technique born in the late 1970s, thanks to the discovery by Otto Warburg that malignant cells have a higher glycolytic rate.Indeed, FDG is an analogue of glucose that is carried across the cell membrane and once phosphorylated, is metabolically trapped.Due to this similarity, 18 FDG can be used as an excellent radiotracer for PET.All the preliminary PET studies have started studying brain disorders and the existence of specific neurotransmitters has introduced various biomarkers, highly specific for different pathologies.
Since the 1980s, after the discovery that many tumoral lesions are associated to an increased uptake of glucose, the application of PET, using 18 FDG, has gained a progressive central role in the oncological field, first detecting and staging lung tumors, subsequently including thyroid, breast, lymphoma, colorectal, esophageal cancer, and melanoma.
To characterize glucose metabolism, a standardized uptake value (SUV) was created, identifying into the lesion a region of interest (ROI) dividing the value by the injected activity and then dividing it by patients' body weight.
Through the years, the resolution of PET images has rapidly improved, until the combination with CT scanners and MRI guarantees an outstanding quality of images (Rohren et al. 2004).
The most used radiotracers that have detected the highest number of incidentalomas are the following: • 18F-fluoro-2-deoxy-dglucose (FDG) is the most used radiotracer but not the only one, developing several radiopharmaceuticals highly specific for different tissues and part of the body.It is still most used in detection of breast lesions, pituitary lesions.• Several case series have reported the role of FDG in the identification of pituitary lesions, mostly macroadenomas (Bertagna et al. 2019).Nevertheless, in case of ACTH or GH microadenoma, aminoacidic PET tracer has shown an undeniable superiority.• Thyroid incidentalomas detection using this methodic was largely investigated, especially by Hsieh et al. and by King et al. (the last one reported the lowest number of incidentaloma using this radiotracer, probably due to a lower risk of thyroid disease related to the geographical area examined) (King et al. 2007).• In the study of Kang et al. (2009) (Hodolic et al. 2014).This observation has clearly proven the pivotal role of "PAIN" findings.
• 11 C methionine and 11 C acetate are also valuable amino acids used as positron-emitting isotopes for the evaluation of prostate cancer and brain tumors (Rohren et al. 2004).Furthermore, another nuclear medicine methodic, the whole-body gallium-67 scintigraphy, is routinely performed to evaluate localization of source of fever in cases of fever of unknown origin (FUO), sarcoidosis, tuberculosis, retroperitoneal fibrosis, spinal osteomyelitis, and other conditions.(Punch et al. 2006;Hirano et al. 1993) Punch et al. incidentally discovered an abnormal focus of tracer uptake in the retroareolar region of the right breast during a whole-body gallium-67 scintigraphy to detect an occult infection.Subsequent biopsy of the right breast lesion revealed an invasive ductal carcinoma.(Punch et al. 2006).

Future direction and limitation
In the wide and potential application of PET, there are still some technical limitations that may be considered.For example, the use of radiations in humans is limited by reluctance and fear of radiation absorption, despite the proven of radiolabeled tracers.This issue has strongly limited the use of this imaging technique, especially as screening in healthy patients.
In the future, the use of kinetic signatures and the improvement of spatial resolution could lead to detect existing disease expressed as a separate tracer kinetic element, below the spatial resolution of the scanner.This improvement could be applied both in infection and in oncology (Jeong et al. 2010).
Moreover, the increasing use of PET in the oncological field should require shorter time per patient, restricting the volume of patients scans.For this reason, the goal should be obtaining more sensitive whole-body PET scanners, to process more patients in less time.
Another goal that may be achieved in the upcoming future is to significantly promote the role of theranostic (i.e., a combination of therapy and diagnostic) in all fields of PET-based oncology (Jeong et al. 2010;Jones and Townsend 2017).

Conclusion
Nuclear imaging techniques play a pivotal role in the detection of incidentalomas, offering crucial insights that often lead to significant changes in patient management strategies.The findings from this systematic review underscore the high sensitivity of modalities such as PET/CT, particularly with FDG and choline tracers, in uncovering unexpected lesions across various malignancies.With thyroid, gastrointestinal, and pulmonary sites being commonly affected, the implications of incidentaloma detection extend beyond mere diagnosis, often prompting immediate adjustments in therapeutic approaches.The integration of nuclear imaging into routine oncological follow-up protocols holds immense promise for enhancing patient care and tumor control.However, future advancements in spatial resolution and the continued exploration of theranostic applications are warranted to further optimize the clinical utility of these techniques.Overall, the growing body of evidence presented here underscores the indispensable role of nuclear imaging in modern oncology, paving the way for more personalized and effective patient management strategies.

Table 2
Summarizes the indication for nuclear medicine imaging and the number of incidentalomas detected as 41.4.68 Ga-DOTATATE PET/CT and 68 Ga-DOTATOC also demonstrated varied SUV values, highlighting the diverse metabolic activity detected across different imaging modalities.These SUV values vary significantly across different imaging techniques and types of lesions, underscoring the importance of modality-specific interpretation of SUV measurements in clinical practice.