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

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.

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The following Mesh (Medical Subject Headings) terms were used:

“PET FDG AND incidentalomas”, “Positron emission tomography FDG AND incidentalomas”, Whole body PET FDG AND incidentalomas”, “Whole body positron emission tomography FDG AND incidentalomas”, “PET FDG brain AND incidentalomas”, “brain AND PET FDG AND incidentalomas”, “SPECT AND incidentalomas”, “whole body AND scintigraphy AND radioiodine AND incidentalomas”, “Gallium scintigraphy AND incidentalomas”, “Scintigraphy AND Gallium AND incidentalomas”, “Scintigraphy AND Gallium AND incidental tumor”, “Octreoscan AND incidentalomas”, “Octreoscan AND incidental tumor”, “Octreoscan AND incidental lesion”, “111 In-pentetreotide Scintigraphy AND incidentalomas”, “Scintigraphy AND Octreotide AND incidentalomas”, “met PET AND incidentaloma”, “c-met AND incidental”, “c methionine AND incidental”, “methionine PET AND incidentaloma”, “methionine PET AND incidental”, “18 f choline PET AND incidentaloma”, “18 f-choline PET AND incidental”, “choline PET AND incidentaloma”, “choline PET AND incidental”, “choline PET AND incidental lesion”, “choline PET AND incidental tumor”, “choline PET AND incidental uptake”, “68Ga-PSMA PET/CT AND incidentalomas”.

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.

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.

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.

Data extracted from each study were (1) authors, (2) year of publication, (3) number of patients included, (4) sex, (5) age, (6) nuclear medicine imaging modality, (7) study design, (8) reason to perform nuclear medicine imaging modality, (9) number of incidentaloma(s), (10) site(s) of incidentaloma(s), (11) primitive/secondary lesions, (12) histology of incidentaloma(s), (13) timing from surgery, (14) management of incidentaloma(s), (15) change in therapeutic strategy (whenever reported), (16) median follow-up, (17) Standardized Uptake Value (SUV).

The initial search yielded 931 results. After duplicate removal (452) and screening by title, 291 articles were excluded because they did not meet the inclusion criteria. After a detailed examination of these 188 studies, 95 papers were excluded because the full text wasn’t available (31), the abstract was not pertinent (42), and they were not in English language (22). Hence, a total of 92 studies were included in this literature review. (Fig. 1) (Panareo et al. 2021; Papadakis et al. 2018; Tiktinsky et al. 2011; Gamberini et al. 2011; Cava et al. 2003; Albano et al. 2019, 2017, 2022; Takesh and Adams 2013; Ciappuccini et al. 2018, 2019; Leiris et al. 2018; Florimonte et al. 2016; Cuppari and Evangelista 2018; Tuscano et al. 2014; Hugentobler et al. 2017; Malamitsi et al. 2017; Bagni et al. 2015; Burgers et al. 2018; Treglia et al. 2013, 2015, 2014; Maffione et al. 2016; Cimitan et al. 2013; Vadrucci et al. 2016; Lalire et al. 2016; Calabria et al. 2013; Eccles et al. 2013; Aziz et al. 2015; Imperiale et al. 2013; Paudel et al. 2019; Goineau et al. 2015; Paone et al. 2013; Agrawal et al. 2015; Parekh et al. 2017; Jozanovic and Huic 2022; Freesmeyer et al. 2014; Cegla et al. 2022; Mangili et al. 2019; Sollini et al. 2016; Dondi et al. 2020; Bertagna et al. 2014a, 2013, 2014b; Mapelli et al. 2012; Ouattara et al. 2017; Garzon et al. 2014; Fallanca et al. 2011; Ambrosini et al. 2006; Sasikumar et al. 2017; Demirkol et al. 2017; Leondi Valotassiou et al. 2005; Mannelli et al. 2017; Villa et al. 2003; Punch et al. 2006; Hirano et al. 1993; Al-Hakami et al. 2011; Wan et al. 2019; Zhai et al. 2010; Targe and Basu 2015; Makis and Ciarallo 2017; Kang et al. 2003; Marko et al. 2020; Mihatsch et al. 2021; Makis et al. 2015; Chan et al. 2022; Cohen et al. 2009; Baldane et al. 2015; Seo et al. 2015; Young et al. 2017; Cheen Hoe et al. 2014; Bosch-Barrera et al. 2009; Mullangi et al. 2021; Liu et al. 2020; Inanir et al. 2019; Alçin et al. 2019; Plouznikoff et al. 2019; Pfob et al. 2019; Militano et al. 2019; Vaz et al. 2018; Malik et al. 2018; Farolfi et al. 2018; Singh et al. 2018; Krishnaraju et al. 2018; Dias and Bouchelouche 2018; Patel et al. 2017; Lawhn-Heath et al. 2017; Bilgin et al. 2016; Chan and Hsiao 2016; Lasocki et al. 2016; Maffei et al. 2012; Cleary et al. 2016).

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).

Patients’ demographics and main characteristics are summarized here. (Suppl. 2).

All the selected records were used to structure the database to evaluate the role of nuclear medicine imaging modalities in detecting incidental lesions and their impact on patients’ management. Nuclear medicine imaging modalities were different:

The clinical series included 64,884 patients. The total number of incidentalomas detected was 611 (0.9%). 3517 (5.4%) patients were men and 2645 (4%) were women. (Table 1) Sex was not reported in 3 studies (58,722 patients, 91%). The M: F ratio was 1.3:1. The mean age was 64.1 years.

Of the incidentalomas detected, 611 were primitive lesions and the most common site was the thyroid.

The updated analysis of 611 incidentalomas detected across various nuclear medicine imaging modalities revealed diverse findings. Sestamibi SPECT/TC identified 1 incidentaloma (0.16%) in the pulmonary area, while Sestamibi TC detected 8 incidentalomas (1.31%) in the pituitary gland, liver, and submandibular gland. There was a single incidentaloma (0.16%) of myelolipoma found using 99-Tc SPECT/TC, and 47 incidentalomas (7.69%) in the adrenal gland by I-131 iodomethyl-norcholesterol (131I-NP-59 [NORCHOL-131]; CIS SPECT). 18F choline PET/CT detected 9 incidentalomas (1.47%) in the thyroid. Furthermore, 18F choline PET identified 47 incidentalomas (7.69%) in various sites, including thymic carcinoma, papillary thyroid carcinoma, large B-cell lymphoma, ischiatic solitary plasmocytoma, salivary gland carcinoma, high-grade (G3) mucinous colon carcinoma, breast cancer, acoustic neurinoma, colorectal cancer, pituitary macroadenoma, Leydig cell tumor in the testis, left tonsil squamous cell carcinoma, right breast carcinoma, colon carcinoma, pulmonary NET, adrenocortical adenoma, brain plasma cell neoplasm, lymph node Hodgkin lymphoma, thyroid Hürthle cell adenoma, neurofibroma in S2 to S4 sacral nerve roots, bladder carcinoma, parathyroid adenoma, schwannoma near the Achilles tendon, laryngeal squamous cell carcinoma, and lung melanoma.

11C choline PET/CT found 7 incidentalomas (1.15%) including esophageal squamous cell carcinoma, frontal lobe meningioma, parathyroid adenoma, papillary thyroid carcinoma, inguinal lymph node large B-cell lymphoma, thymoma, and ilium plasmocytoma. 68Ga PSMA-PET/CT detected 31 incidentalomas (5.07%) across various sites, including the stomach, medullary thyroid cancer, primary pancreatic cancer, vestibular schwannoma, liposarcoma, GIST, thymic carcinoma, pheochromocytoma, thymoma, lumbar schwannoma, left orbitofrontal region, and right superior cerebellar lesion.

In-111 pentetreotide Scintigraphy identified 3 incidentalomas (0.49%) of meningioma, medullary thyroid cancer, and thyroid follicular cancer, while 67 Gallium Scintigraphy found 2 incidentalomas (0.33%) of invasive ductal carcinoma and meningioma.

Whole-body FDG-PET/CT was the most prolific, detecting 115 incidentalomas (18.82%) across a wide range of sites including the thyroid, parotid, cervical lymph node, lungs, head and neck region, colon, pelvis, adrenal glands, bone, esophagus, inguinal area, kidney, liver, mediastinum, prostate gland, rectum, and stomach.

68Ga-DOTATATE identified 2 incidentalomas (0.33%) of tonsillar lesion and pelvic, while 68Ga-DOTATATE PET/CT detected 19 incidentalomas (3.11%), including pituitary uptake, retroperitoneal liposarcoma, vestibular schwannoma, left internal obturator muscle, parathyroid gland, liposarcoma, GIST, thymic carcinoma, pheochromocytoma, thymoma, lumbar schwannoma.

A Gallium-68 DOTA-octreotate CT/PET found 1 incidentaloma (0.16%) in the left cerebellar hemisphere near the vermis, and 68Ga-DOTATOC PET/CT identified 1 incidentaloma (0.16%) of meningioma. Additionally, whole-body FDG-PET/CT reported 1 incidentaloma (0.16%) of pituitary gland.

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).

After finding these lesions, 53 studies (58%) including 358 incidentalomas (59%) reported a change in therapeutic strategy, 4 studies (4.3%) including 74 incidentalomas (12%) did not change strategy, and, finally, 34 studies (37%) including 179 incidentalomas (29%) did not report these details. (Table 3) Incidentalomas were treated with chemotherapy, radiotherapy, a combination of radio and chemotherapy, surgery, Gamma Knife or only with follow-up. (Table 4) The median follow-up of the patients was 0.5 years.

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 reaching as high 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.

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, ¹⁸FDG 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 ¹⁸FDG, 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:

Scintigraphy is a nuclear medicine diagnostic test, where radioisotopes attached to drugs that travel to a specific organ or tissue are internalized and the emitted gamma radiation is captured to form two-dimensional images. This methodic with the somatostatin receptor agent In-111 pentetreotide is most useful to detect patients with neuroendocrine tumors (APUDoma), but the tumor-targeting potential of this radiopharmaceutical in other types has been also described in literature. (Leondi Valotassiou et al. 2005; Mannelli et al. 2017; Villa et al. 2003) Villa et al. described a peculiar case of a 38-year-old female patient with lung carcinoid that underwent scintigraphy with In-111 pentetreotide, positive in the known lung tumor and incidentally revealed uptake in a thyroid nodule, with a final diagnosis of follicular cancer. (Villa et al. 2003) Leondi et al. also reported an uptake of In-111 in the right cerebral hemisphere, consisting of meningiomatosis. (Leondi Valotassiou et al. 2005).

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).

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).