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Background Histopathology is the reference standard for diagnosing liver metastases of neuroendocrine tumors (NETs). Somatostatin receptor-positron emission tomography / computed tomography (SSR-PET/CT ) has emerged as a promising non-invasive imaging modality for staging NETs. We aimed to assess the diagnostic accuracy of SSR-PET/ CT in the identification of liver metastases in patients with proven NETs compared to histopathology. Methods Histopathologic reports of 139 resected or biopsied liver lesions of patients with known NET were correlated with matching SSR-PET/CTs and the positive/negative predictive value (PPV/NPV ), sensitivity, specificity, and diagnostic accuracy of SSR-PET/CT were evaluated. PET/CT reading was performed by one expert reader blinded to histopathology and clinical data. Results 133 of 139 (95.7%) liver lesions showed malignant SSR-uptake in PET/CT while initial histopathology reported on ‘liver metastases of NET´ in 127 (91.4%) cases, giving a PPV of 91.0%. Re-biopsy of the initially histopathologically negative lesions (reference standard) nevertheless diagnosed ‘liver metastases of NET’ in 6 cases, improving the PPV of PET/CT to 95.5%. Reasons for initial false-negative histopathology were inadequate sampling in the sense of non- target biopsies. The 6 (4.3%) SSR-negative lesions were all G2 NETs with a Ki-67 between 2–15%. Conclusion SSR-PET/CT is a highly accurate imaging modality for the diagnosis of liver metastases in patients with proven NETs. However, we found that due to the well-known tumor heterogeneity of NETs, specifically in G2 NETs approximately 4–5% are SSR-negative and may require additional imaging with [ F]FDG PET/CT. Keywords NET, SSR, PET/CT, MRI, Liver metastases *Correspondence: Department of Internal Medicine 4, University Hospital, LMU Munich, Freba Grawe 81377 Munich, Germany firstname.lastname@example.org Interdisciplinary Center of Neuroendocrine Tumors of the Department of Radiology, University Hospital, LMU Munich, GastroEnteroPancreatic System (GEPNET-KUM, ENETS certified Center of Marchioninistr. 15, 81377 Munich, Germany Excellence), University Hospital, LMU Munich, 81377 Munich, Germany 2 5 Department of Nuclear Medicine, University Hospital, LMU Munich, Department of Pathology, University Hospital, LMU Munich, 81377 Munich, Germany 81377 Munich, Germany © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Fabritius et al. Cancer Imaging (2023) 23:92 Page 2 of 8 Background assessment of non-target lesions. Additionally, results Neuroendocrine tumors (NETs) arise from cells of the prior to re-biopsy are presented for a better overview endocrine system found throughout the body and occur of non-target biopsies. Histopathology was obtained by most commonly in the gastrointestinal tract, pancreas CT- or ultrasound-guided biopsy in 67% (n = 92), surgi- and lungs [1, 2]. Due to their rarity and heterogeneity, cal resection in 32% (n = 45) and hemihepatectomy in 1% diagnosis and management of NETs can be challenging (n = 2) of the cases. The reference standard was compared [3–5]. Since the liver represents the most common site in a lesion-based analysis of the correlating 139 SSR- for metastatic disease in NETs and is associated with PET/CTs by one expert reader (> 10 years of experience) significant morbidity and mortality, early diagnosis and by labeling all liver lesions with malignant SSR-uptake accurate staging is essential for optimal patient manage- consistent with NET metastasis, blinded to histopathol- ment and improved outcome [6–8]. ogy and clinical data. The index lesion was defined as the Historically, histopathology has been the reference lesion which was biopsied and correlated to SSR-PET/ standard for diagnosing liver metastases of NETs. How- CT. In cases where the expert did not label the index ever, this approach has limitations, including potential lesion on PET/CT as a NET metastasis (n = 6), the expert sampling errors and the inability to assess the entire liver was unblinded and the PET/CT was reviewed together tissue. Moreover, biopsy procedures are invasive and with additional available information, in particular with a costly. In recent years, somatostatin receptor positron generally available corresponding liver MRI. emission tomography/computed tomography (SSR-PET/ CT) has emerged as the guideline-recommended non- SSR-PET/CT imaging invasive imaging modality for diagnosing and staging SSR-PET/CT scans were acquired on a Biograph 64 of highly differentiated NETs. SSR-PET/CT uses radio - TruePoint w/TrueV and Biograph mCT Flow 20-4R PET/ labeled SSR-analogs, which bind to SSR that are highly CT scanner (Siemens Healthineers, Erlangen, Germany). expressed in NETs. According to the World Health Orga- PET/CT scans were initiated 67 ± 11 min after adminis- nization (WHO), tumor classification of NETs of the gas - tration of 218 ± 33 MBq [68Ga]Ga-DOTA-TATE PET/ troenteropancreatic system is based on the morphology CT and 62 ± 10 min after administration of 231 ± 20 and proliferation index (Ki-67) into grade 1–3 . Grade MBq [68Ga]Ga-DOTATOC. Data on tracer adminis- 1 (Ki-67 < 2%) and grade 2 (Ki-67 3-20%) NETs have high tration was not available in one case. After intravenous somatostatin receptor (SSR) expression, whereas grade 3 injection of 1.5 times the body weight of contrast agent (Ki-67 > 20%) NETs show higher glucose metabolism and (Ultravist 300, Bayer Vital GmbH, Leverkusen, Ger- lower SSR-expression [6, 10]. many or Imeron 350 mg/mL, 2.5 ml/s, Bracco Imaging The aim of this study was to compare the diagnostic Deutschland GmbH) diagnostic venous-phase CT scans accuracy of SSR-PET/CT in the identification of liver of the neck, thorax, abdomen, and pelvis (100–190 mAs; metastases of NET patients in a lesion-based manner 120 kV) were acquired. Patients received diagnostic CT with histopathology as the reference standard. scans without contrast enhancement in cases of known severe allergic reactions to iodinated contrast agent, renal Methods impairment/failure, or hyperthyroidism. Image construc- Study design and patient cohort tion was automatically performed using built-in software. Our institutional database was screened retrospectively 3 mm-slice reconstructions were used for reading. SSR- for the term SSR imaging studies between 2006 and expression in PET/CT was assessed visually using the 2021 and a total of 8077 results were found. These imag - Krenning score. ing studies were assigned to a total of 2605 patients. We excluded all studies listed multiple times to one patient, Statistical analysis studies of patients < 18 years or of other entities than All continuous variables were expressed as mean and G1/G2 NETs of the gastroenteropancreatic and bron- standard deviation (SD). For statistical analysis, diagnos- chopulmonary tract (e.g., meningioma, paraganglioma) tic accuracy of SSR-PET/CT was tested using positive in the further analysis. Of the therefore remaining 1584 predictive value (PPV), negative predictive value (NPV), patients, 1429 patients without histopathology of the sensitivity and specificity. Additionally, exact 95% confi - liver were excluded. Thus 119 patients with differenti - dence intervals (CI) were calculated for all values. ated NET (grade 1/2) with a total of 139 lesions with correlating histopathology (obtained within a maximum Results of 6 months) were included for the final analysis. A flow Patient characteristics chart of the patient selection is presented in Fig. 1. The Patient characteristics are summarized in Table 1. Biopsy reference standard was defined as histopathology after led to the diagnosis of NET in 33/139 (24%) of cases. re-biopsy in cases of initially negative results due to The remaining 106/139 (76%) biopsies were performed Fabritius et al. Cancer Imaging (2023) 23:92 Page 3 of 8 Fig. 1 Flow chart of patient selection Table 1 Patient characteristics for molecular analysis or exclusion of secondary Patient characteristics n (%) malignancies. Sex Female 47 (39%) Diagnostic accuracy of PET/CT in the detection of liver Male 72 (61%) metastases Location of primary 133 of 139 (95.7%) liver lesions were detected and labeled Gastroenteropancreatic 104 (87) as NET metastases with malignant SSR-expression. The Pancreas 43 (41) reference standard histopathology after re-biopsy of ini- Small intestine 49 (47) tially negative results reported on ‘liver metastases of Colon 10 (10) NET’ in 127 of 139 (91.4%) cases of which 34 (27%) were Liver 2 (2) metastases of G1 NET and 93 (73%) of G2 NET, result- Lung 10 (8) ing in a PPV of 95.5%. Before re-biopsy, the PPV of PET/ CUP 4 (3) CT was 91.0%. Hepatic involvement detected by SSR- Kidney 1 (1) PET/CT and histopathology after first biopsy and re- SSR-analogs biopsy is presented in Tables 2 and 3. An overview of all [ Ga]Ga-DOTATOC 89 (64%) 68 results (PPV, NPV, sensitivity and specificity for PET/CT [ Ga]Ga-DOTA-TATE 50 (36%) vs. histopathology before and after re-biopsy is shown in SSR, somatostatin receptor. Table 4. Mean age ± SD was 63.0 ± 12. 3 years . Fabritius et al. Cancer Imaging (2023) 23:92 Page 4 of 8 Table 2 Hepatic involvement detected by SSR-PET/CT and Histopathologically confirmed liver metastases of NET histopathology after first biopsy without correlate in SSR-PET/CT Histopathology In 6 (4.3%) cases, liver metastases of NET were reported SSR-PET/CT Positive Negative n total by histopathology, but the corresponding lesions did not Positive 121 12 133 show any SSR expression in PET/CT. Negative 6 0 6 Two patients with NET of the small intestine (Ki-67 n 127 12 139 total 2%, 3.4 × 2.6 cm and Ki-67 10%, 1.6 × 1.3 cm) showed SSR- negative liver metastases but were [ F]FDG-positive in Table 3 Hepatic involvement detected by SSR-PET/CT and 18 additional [ F]FDG PET/CT (SUVmax 4.9 and SUV- histopathology after re-biopsy max 8.9). One patient showed SSR-uptake of the pri- Histopathology mary tumor in the small intestine but was SSR-negative SSR-PET/CT Positive Negative n total for liver (Ki-67 8%) and histologically confirmed ovar - Positive 127 6 133 ian metastases, which again were positive in additional Negative 6 0 6 [ F]FDG PET/CT (2.8 × 2.7 cm, SUVmax 5.8; see Fig. 3). n 133 6 139 total One patient with a NET of the small intestine (Ki-67 5%) received radioembolization of the liver metastases Table 4 PPV, NPV, sensitivity, specificity and diagnostic accuracy and was SSR-negative, whereas MRI of the liver showed for SSR-PET/CT. PPV, positive predictive value; NPV, negative residual arterial hypervascularization (7.5 × 5.4 cm). predictive value. Another patient with a carcinoid of the lung (Ki-67 15%, Biopsy Re-biopsy 2.4 × 1.6 cm) and one patient with a NET of the pancreas (reference (Ki-67 5%, 2.4 × 2.0 cm) showed SSR-negative liver metas- standard) tases. Table 5 gives an overview on the results of the his- PPV 91.0% (95%CI: 95.5% (95%CI: 84.8%, 95.3%) 90.4%, 98.3%) topathological examinations of those lesions. NPV 0% (95%CI: 0%, 0% (95%CI: 45.9%) 0%, 45.9%) Sensitivity 95.2% (95%CI: 95.5% (95%CI: Discussion 90.0%, 98.3%) 90.4%, 98.3%) In this retrospective study, we performed a liver Specificity 0% (95%CI: 0%, 0% (95%CI: lesion-based comparison of histopathologic reports 26.5%) 0%, 45.9%) and SSR-PET/CT ([ Ga]Ga-DOTATOC and Accuracy 87.1% (95%CI: 91.4% (95%CI: [ Ga]Ga-DOTA-TATE) findings in patients with diag - 80.0%, 92.1%) 85.4%, 95.5%) PPV, positive predictive value; NPV, negative predictive value nosed NET. Our results demonstrate high diagnostic NPV and Specificity are both recorded as 0% due to the deliberate study design accuracy of SSR-PET/CT in the identification of liver focusing on a patient cohort with a notably high prevalence of liver metastases. metastases of NET patients with an excellent PPV of 91.0% and an even higher PPV of 95.5% when compared Additionally, diagnostic accuracy was calculated for to re-biopsy of initially negative histopathological results. G1 and G2 NETs separately and showed similar excellent Several previous studies have demonstrated the high results with a PPV of 100%, respectively. An overview on diagnostic accuracy of SSR-PET/CT in the evalua- all results (PPV, NPV, sensitivity, specificity, and diagnos - tion of NETs. In a large study of 728 NET patients, tic accuracy) are presented in the supplements in Tabe S1 [ Ga]Ga-DOTA-TATE PET/CT showed high sensitivity, and S2. specificity, accuracy, positive predictive value, and nega - tive predictive value (97.0%, 95.1%, 96.6%, 98.5%, and SSR-positive liver lesions without histopathological 90.4%) in the detection of overall NET lesions . Spe- correlate cifically identifying hepatic involvement in NET patients, In 12 cases, all of which were marked by the reader as similar high diagnostic accuracy was reported for SSR- NET metastases on PET/CT, no tumor tissue could be PET/CT compared to the reference standard liver MRI detected by histopathology. A re-biopsy was performed with a sensitivity of 97.0% and a specificity of 97.7%, a in 8 of 12 cases: in 6 of those cases, liver metastases of a PPV of 99.0% and NPV of 93.0% . Moreover, SSR- NET (G1/2) were finally diagnosed, whereas 2 of the re- PET/CT was found to have an important value in the biopsies confirmed negative histopathological results. In diagnosis of pulmonary neuroendocrine tumors (carci- one case, the negative histopathological result was con- noids) and its distant metastases [13, 14]. However, one firmed by a further re-biopsy, whereas the second case patient in our cohort with a carcinoid of the lung and a was not further followed. A patient example is presented Ki-67 of 15% (G2) showed SSR-negative liver metastases. in Fig. 2. Thus, a low rate of false-positive PET findings Haug et al. also reported on low tracer of liver metastases seems possible. Fabritius et al. Cancer Imaging (2023) 23:92 Page 5 of 8 Fig. 2 Initially false-negative histopathological result of a liver metastasis in a 64 year old patient with a newly diagnosed NET G1 (Ki-67 2%) of the pan- creas. On CT (first row, left image, venous phase), hepatic metastasis in segment 8 with 2.8 × 2.8 cm was clearly delineated with enhanced [ Ga]Ga-DOTA TATE-uptake in PET (first row, right image). First biopsy was negative, whereas second biopsy confirmed liver metastasis of NET G1 on histopathological examination (second row, both images) in a patient with atypical carcinoid tumor of intermediate In 6 (4.3%) cases, the index lesion was not labeled as grade . NET metastasis in SSR-PET/CT, however, subsequent In 12 (8.6%) SSR-positive lesions, no tumor tissue was dynamic, contrast-enhanced MRI of the liver unequivo- detected by initial histopathology in our cohort, whereas cally confirmed these lesions as metastatic NETs. This tumor cells of NETs were identified after re-biopsy in nd fi ing emphasizes the ongoing essential role of liver MRI most cases (6/8 cases). Thus, the underlying reasons in specific cases. Notably, all 6 of these lesions were cat - were most likely inadequate sampling in the sense of egorized as G2 in the corresponding histopathological non-target biopsies. This finding emphasizes that the reports, with Ki-67 values ranging between 2% and 15%. absence of detectable metastatic lesions on liver biopsy The observed heterogeneity of SSR-expression patterns in does not necessarily rule out the presence of liver metas- NETs is likely attributed to the inherent tumor/metastatic tases of NET patients. Tumor heterogeneity of NETs variability, resulting in diverse SSR-expression profiles is well known, and low Ki-67 may be challenging to be even within the same patient across different lesions [17, detected on histological examinations. Moreover, not 18]. Furthermore, it is well known that NETs of low dif- all liver metastases are easily accessible for biopsies, for ferentiation lack SSR-expression and SSR-PET/CT has example if located close to large vessels. In consider- low sensitivity but can be localized by [ F]FDG PET/ ation of these possible false-negative biopsy results, his- CT [2, 19, 20]. Liver metastases from NETs are often tologic verification of PET-positive liver lesions appears diagnosed by CT- or ultrasound-guided biopsy, in which redundant in cases of patients with histologically proven tumor tissue is obtained randomly from a specific lesion, NETs, and functional imaging with SSR-PET/CT might depending on accessibility, and the Ki-67 is determined reduce unnecessary further biopsies. However, one must without targeting regions that may have a higher prolif- be aware that biopsies are nowadays not only used for eration rate . In our analysis, in 2 patients with NET pure histological confirmation of metastases but are also G2 (Ki-67 2% and Ki-67 10%, respectively) additional required for additional molecular diagnostics in preci- [ F]FDG PET/CT was performed and showed high sion medicine . [ F]FDG-uptake indicating intertumoral heterogeneity with tumor cells of lower differentiation. For these cases, Fabritius et al. Cancer Imaging (2023) 23:92 Page 6 of 8 Fig. 3 PET/CT of a 47 year old patient with a NET G2 (Ki-67 8%) of the small intestine. Liver lesion in segment 8 with 2.8 × 2.7 cm without 68 68 [ Ga]Ga-DOTATOC-uptake in SSR-PET/CT (first row). [ Ga]Ga-DOTATOC-uptake of the small intestine (primary site) led to the suspicion of undifferenti - 18 18 ated liver metastases. Additional [ F]FDG PET/CT was performed and showed enhanced [ F]FDG-uptake (SUVmax 5.8) compared to liver parenchyma. 68 18 Left images show fused PET/CT (first row: [ Ga]Ga-DOTATOC PET/CT, second row: [ F]FDG PET/CT, middle images show PET; right images show maxi- mum intensity projections (MIP). of patients, SSR-PET/CT represents a whole-body, one- Table 5 Histopathological results of the 6 liver lesions without stop-shop diagnostic tool for NETs. SSR-uptake in PET/CT Lesion Primary of NET Liver There are various limitations to this study. Firstly, metastases this was a retrospectively conducted single-center study. 1 Small intestine, pT3, pN1 (6/14), L1, V0, local G1, Ki-67 2% The use of SSR-analogues ([ Ga]Ga-DOTATOC and R0, pM1, G2, Ki-67 > 2% 68 [ Ga]Ga-DOTA-TATE) varied across patients and 2 Small intestine, pT3, pN1 (1/13), L1, V1, Pn1, G2, Ki-67 examinations. Nevertheless, previous studies have consis- R1 (liver), pM1, G2, Ki-67 1–15%, 10% tently reported no differences in diagnostic accuracy when 3 Small intestine, pT4, pN2 (13 / 29), pM1c G2, Ki-67 8% evaluating sensitivities and uptake values among different (HEP, PER, OTH), L1, V0, Pn1, R1 SSR-ligands, including considerations of tumor origin and 4 Small intestine, pT2, pN1 (4/31) L0, V0, G2, G2, Ki-67 5% grading [23, 24]. Additionally, the effective doses of both Ki-67 3–4% radiopharmaceuticals are comparable, rendering them 5 Pancreas, pT2, pN0, L0, V0, G1, R0, cM0 G2, Ki-67 5% 6 Carcinoid of the lung, histopathological G2, Ki-67 equivalent even from a radiation dosimetry perspective report on primary not available 15% . Furthermore, not all patients with SSR-negative NET lesions received additional [ F]FDG PET/CT for further a proposed grading scheme which describes the joint diagnostic evaluation. The lack of [ F]FDG PET/CT data results of both, the [ F]FDG- and SSR-PET scans in dual for some SSR-negative patients could potentially influ - tracer imaging (NETPET), showed promising results as ence the overall diagnostic accuracy and completeness a prognostic biomarker and correlated significantly with of our findings. Although we have not directly compared 18 18 overall survival [1, 22]. Therefore, [ F]FDG PET/CT may the diagnostic performance of SSR imaging and [ F]FDG have a clinical role in intermediate grade neuroendocrine PET/CT in this study, acknowledging this limitation is neoplasms based on clinical presentation (e.g., patients essential for a comprehensive understanding of the scope with CT progression or with SSR-negative lesions). and implications of our results. Future studies that incor- Despite above mentioned limitations in a small number porate both SSR imaging and [ F]FDG PET/CT data for all patient groups could offer a more comprehensive Fabritius et al. Cancer Imaging (2023) 23:92 Page 7 of 8 Declarations assessment of the diagnostic capabilities of these imaging modalities in the context of SSR-negative NET lesions. Ethics approval and consent to participate This study, which was conducted according to the Helsinki Declaration of 2013, was approved by the Ethics Committee of the Medical Faculty of the Conclusion Ludwig Maximilian University Munich. Informed patient consent was waived In conclusion, SSR-PET/CT is a highly accurate imag- due to the retrospective nature of the study (project number: 20-1077). ing modality for the diagnosis of liver metastases of NET Consent for publication patients. However, due to the well-known tumor hetero- Not applicable. geneity of NETs, specifically 4–5% of G2 NETs are SSR- Competing interests negative and additional imaging with [ F]FDG PET/CT There is no conflict of interest that could be considered to compromise the or functional imaging-based biopsy is useful to identify impartiality of the research reported. C.J.A has received research contracts higher-grade disease. (Novartis), lecture honorarium (Advacanced Accelerator Applications, Ipsen, Novartis) and advisory board honorarium (Advacanced Accelerator Abbreviations Applications). NET Neuroendocrine tumor >SSR Somatostatin receptor Received: 3 July 2023 / Accepted: 19 September 2023 PET/CT Positron emission tomography/computed tomography G Grade FDG Fluorodeoxyglucose WHO World Health Organization DOTA-TOC DOTA(0)-Phe(1)-Tyr(3))octreotide DOTA-TATE DOTA-0-Tyr3-Octreotate References SD Standard deviation 1. Chan DL, Pavlakis N, Schembri GP, Bernard EJ, Hsiao E, Hayes A, et al. 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Cancer Imaging – Springer Journals
Published: Sep 28, 2023
Keywords: NET; SSR; PET/CT; MRI; Liver metastases
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