Value of [68Ga]Ga-somatostatin receptor PET/CT in the grading of pulmonary neuroendocrine (carcinoid) tumours and the detection of disseminated disease: single-centre pathology-based analysis and review of the literature

Background Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours (PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with [18F]FDG PET/CT in a subgroup of patients. Methods SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available, [18F]FDG PET/CT images were also evaluated. The maximum standardized uptake (SUVmax) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUVmax values were related to the tumour type (TC versus AC) for both SSTR and [18F]FDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUVmax values were compared to the pathological status (N+ versus N−) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed. Results A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed. [18F]FDG PET/CT was available in 46 patients. Analysis of the SUVmax values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUVmax 18.4 vs 3.8; p = 0.003) and significantly higher [18F]FDG uptake in AC compared to TC (median SUVmax 5.4 vs 3.5; p = 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on [18F]FDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/[18F]FDG SUVmax values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for [18F]FDG PET/CT (difference 0.17; 95% confidence interval − 0.03 to 0.38; p = 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed. Conclusion Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for [18F]FDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-022-00900-3.

Background Pulmonary carcinoid tumours (PC), also known as bronchial carcinoid tumours, are a group of well-differentiated, low (typical carcinoid, TC) to intermediate (atypical carcinoid, AC) grade neuroendocrine tumours (NETs), originating from enterochromaffin or Kulchitzky cells in the respiratory tract [1,2]. Of all well-differentiated NETs, around 25% are located in the respiratory tract [1,3,4]. The age-adjusted incidence rate ranges from 0.2 to 2/100000 persons/year in both the USA and Europe [1][2][3][4]. There has been an increase in prevalence over the past decades, regardless of confounding demographic factors [1][2][3]5]. Other types of pulmonary NETs include the high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC), which are classified as different clinico-pathological entities, are characterized by the presence of tumour necrosis and higher mitotic rates and are associated with a worse prognosis [4,6].
Pathologic examination is the cornerstone in the diagnostic assessment of any pulmonary NET, with the recent fifth edition of the WHO nomenclature of thoracic tumours being the current standard for classification [6]. Mitosis and necrosis are the histopathologic features that distinguish TC from AC [6,7]. To provide the TNM staging for PC according to the eighth edition lung cancer stage classification, diagnostic tools vary widely between institutions and countries, with the traditional morphologic computed tomography (CT) still being the gold standard [2,8]. However, CT imaging features of a PC are often nonspecific and are unable to differentiate between a PC, an adenocarcinoma or a squamous cell carcinoma, let alone between TC and AC [7,9]. Also, a correct preoperative pathologic evaluation is generally hard to obtain, and the preoperative differentiation between TC and AC is considered not feasible even if using the Ki67 proliferation index [7,10]. In this context, PET could be seen as a "noninvasive biopsy" and an accurate full TNM staging examination [7,11].
Since several decades, it is known that NETs-in particular if well-differentiated-express high levels of somatostatin receptors (SSTR), specifically subtype 2 [12,13]. In the early 1990s, the first studies with radiolabelled octreotide derivatives showed the potential for in vivo detection of SSTR expression within tumours, raising interest in this new molecular imaging tool [14]. [ 111 In] In-pentetreotide (brand name: Octreoscan ® ) was one of the first widespread functional imaging tools for NETs [15,16]. Over the past two decades, several other somatostatin analogs (SSA) with a higher affinity for SSTR have been developed (DOTATATE, DOTANOC, DOTA-TOC) [17]. These agents can be labelled with gallium-68 ( 68 Ga), a positron emitter that enables PET imaging and thus provides improved image quality and spatial resolution [18,19]. Moreover, novel agents that can be labelled with fluorine-18 or copper-64 will increase the availability of SSTR PET in the near future [20,21]. SSTR PET/ CT imaging proved to visualize nearly 80% of primary PC tumours [1]. Furthermore, it is the most sensitive imaging technique for the detection of metastatic disease, especially regarding bone metastases for which CT can have a low sensitivity [22][23][24][25]. Therefore, SSTR PET/CT is suggested as a basic tool in the TNM staging of PC in most guidelines, together with contrast-enhanced CT of the chest and liver in a late arterial phase [1,26]. For [ 18 F] FDG PET/CT, the detection rate of the primary tumour and metastatic lymph nodes from PC that are reported in the literature vary widely, probably due to the major difference in glucose metabolic activity between TC, AC and high-grade neuroendocrine lung tumours [7,27]. In this way, the combined use of SSTR PET/CT and [ 18 F] FDG PET/CT can be helpful in determining the biology of PC [1,18,28,29].
Therapeutic strategies for PC include resection of the tumour for limited disease, administration of somatostatin analogs for carcinoid syndrome or as first-line systemic antiproliferative treatment in unresectable PCs, and systemic therapy for metastatic disease (everolimus, chemotherapy, peptide receptor radionuclide therapy (PRRT)) [1,2,4,30].
In this study, we firstly wanted to study retrospectively the value of dual (SSTR/[ 18 F]FDG) PET/CT in the assessment of the tumour biology, based on the widely known "flip-flop phenomenon" of high SSTR and low [ 18 F]FDG uptake in well-differentiated tumours and the opposite imaging phenotype in poorly differentiated tumours [31]. Although hilar and mediastinal lymph node involvement is known as one of the most important prognostic factors in PC, no studies have been done to quantitatively assess the diagnostic performance of SSTR PET/CT in the detection of these regional lymph node metastases [32,33]. The most common sites of distant PC metastases are the liver and bones. Therefore, we also wanted to evaluate the pathology-based diagnostic accuracy of SSTR PET/CT with specific emphasis on regional lymph node involvement and on distant metastatic disease, based on a retrospective analysis of the preoperative SSTR PET/ CT images and the pathology reports. As most literature reviews on the diagnostic value of SSTR PET/CT focus on NETs in general, with a strong emphasis on gastroenteropancreatic (GEP) NETs [18], we also provide a literature overview of the diagnostic performance and impact of SSTR PET/CT on the TNM staging for pulmonary neuroendocrine tumours in particular.

Patient selection
This was a retrospective study with prior approval of the Research Ethics Committee UZ/KU Leuven (study number MP015178). Databases of the nuclear medicine department and the department of thoracic surgery were searched for patients who had a SSTR PET/CT and a standard CT in the context of staging or follow-up for a histologically proven NET of the lung in the period from January 2007 (start of SSTR PET/CT at our centre) to May 2020 (cut-off date). Only SSTR PET/CTs performed in our institution were included. The absence of an [ 18 F] FDG PET/CT or the execution of [ 18 F]FDG PET/CT in an external centre was not considered an exclusion criterion. Patient characteristics, clinical presentation, laboratory results, histopathology, diagnostic imaging, decision of the multidisciplinary tumour board, treatment and follow-up were noted.

Positron emission tomography/computed tomography (PET/CT) protocols and image analysis
All SSTR PET/CTs were performed on a dedicated hybrid scanner (Biograph 16-slice HiRez LSO PET/ CT (Siemens, Erlangen, Germany), Biograph 40 True-Point PET/CT (Siemens, Erlangen, Germany) or Discovery MI4 PET/CT (GE, Milwaukee, WI, USA)). These cameras were EARL accredited for [ 18 F]FDG and cross-calibrated for gallium-68. However, they are not accredited by the recently launched EARL accreditation programme for gallium-68. The tracer used was initially [ 68 Ga]Ga-DOTATOC (synthesis as described) [34], with a switch to [ 68 Ga]Ga-DOTATATE from the end of 2012 onwards. If an [ 18 F]FDG PET/CT was performed during diagnostic work-up with a maximum interval of 6 months from the SSTR PET/CT, these data were retrieved for paired analysis. A paired analysis was only done if no therapeutic interventions occurred during the time interval between [ 18 F]FDG and SSTR PET/CT. All images were re-evaluated using MIM software v 7.0 (MIM Software Inc., Cleveland, Ohio, USA) with annotation of the maximum standardized uptake value (SUV max ) in the primary tumour, in all hilar and mediastinal lymph node stations that were pathologically evaluated and in each metastatic organ (distant lymph nodes, liver, bone, etc.). In patients with multiple metastatic lesions in one organ, the SUV max of the most [ 68 Ga]Ga-DOTA-SSA-or [ 18 F]FDG-avid lesion was noted.

Pathological evaluation
Systematic nodal dissection with histopathologic evaluation is part of the standard protocol during resections for PC in our centre, in line with the European Society of Thoracic Surgeons (ESTS) guidelines [35]. In agreement with the WHO criteria, the pathological specimens had been evaluated and classified as TC, AC or LCNEC based on the mitotic rate and the presence or absence of necrosis [6]. If resection or biopsy occurred in an external institution, we requested the reports and the classification as TC, AC or LCNEC was recorded. As only a single patient with LCNEC had the primary tumour in situ at the time of imaging, the tumoural SUV max analysis was restricted to pathology-proven TC/AC tumours. Resected lymph nodes were labelled according to the "International Association for the Study of Lung Cancer (IASLC)" lymph node map [36]. The pathological evaluation of lymph nodes in each resected and examined mediastinal and/or hilar station, was noted for each resected station from the reports (N + /N-). For these lymph node stations, SUV max values were calculated on the preoperative SSTR PET/ CT, using the CT boundaries of the IASLC map.

Statistical analysis
Frequencies and percentages were used to analyse qualitative variables, whereas medians were reported to descriptively analyse the quantitative variables. The Mann-Whitney test was used to test differences in tumoural SUV max values between TCs and ACs for both SSTR and [ 18 F]FDG PET/CT. A scatter plot was made to illustrate the association between paired tumoural SUV max values (TC/AC) on [ 18 F]FDG and SSTR PET/ CT. The association of a metric and a dichotomous variable was analysed using receiver operating characteristics (ROC) curves, both for the detection of lymph node metastases as for the detection of TC on SSTR PET/ CT and of AC on [ 18 F]FDG PET/CT. The optimal cutoff SUV max value to differentiate between AC and TC was defined by the maximal Youden's index (sensitivity + specificity − 1) on the ROC curves of non-paired SUV max values for the detection of TC on SSTR PET/ CT and of AC on [ 18 F]FDG PET/CT. To calculate sensitivity and specificity for N + disease from TC on SSTR PET/CT, an SUV max cut-off value was determined based on the maximal Youden's index on the ROC analysis of the non-paired SSTR PET/CT SUV max values in the hilar and mediastinal nodes in patients with TC. To compare SUV max values in metastatic lesions on SSTR PET/CT and on [ 18 F]FDG PET/CT, a linear mixed model was used for data analysis, including a random intercept to account for clustering by paired data. The analysis was performed on a log-transformed outcome variable. All tests were performed as two-sided tests, and p values of less than 0.05 were considered significant. The analyses were carried out through IBM SPSS Statistics (version 27) and SAS software (version 9.4 of the SAS System for Windows).

Literature search
A literature search was performed using The National Center for Biotechnology Information PubMed online database. The following key words were used for selection of studies: "pulmonary carcinoid" or "bronchial carcinoid" AND "DOTA PET". The references from retrieved papers were also searched for suitable publications. Ten publications were deemed suitable based on the following inclusion criteria: original research, SSTR PET/ CT performed for pathologically proven PC and number of patients five or more.

Results
A total of 87 patients were withheld from the databases. One patient was excluded because of the diagnosis of a primary pulmonary paraganglioma on final pathological evaluation, yielding a total of 86 patients with pulmonary NETs. Patient and tumour characteristics are listed in Table 1. Nearly two-thirds of the patients were female (55/86; 64%), and the median age of the patient population was 60 years (range 15-84).
Sixty-two patients (72%) underwent the [ 68 Ga]Ga-SSTR PET/CT during primary staging of the PC, 2 patients (2%) during screening for NETs in the context of adrenocorticotropic hormone (ACTH) overproduction, 3 patients (4%) in the context of increased serum chromogranin levels after resection of a PC in the past, and 19 patients (22%) during follow-up for metastatic disease. The most frequent location of the primary tumour was the lower lobe of the right lung. Forty-nine of the 62 patients in the staging group (79%) and each of the 2 patients in the ACTH screening group underwent surgical resection of the primary tumour, yielding the diagnosis of TC in 43 patients, of AC in 7 patients and of LCNEC in 1 patient. Of the patients that underwent the SSTR PET/CT after resection of a PC in the past (N = 16), 8 had a primary TC, 6 a primary AC and 2 a carcinoid not otherwise specified (NOS). Taken together, resection specimens revealed 51 TCs, 13 ACs, 1 LCNEC and 2 carcinoids NOS in total. In 19 patients, no resection of the primary tumour occurred but pathology of the tumour and/or metastatic lesions was available through biopsy and was suggestive for TC in 11 patients, for AC in 6 patients and for LCNEC in 2 other patients. The primary tumour was in situ when performing the SSTR PET/CT in 70 of the 86 patients. However, 6 more patients were excluded for the SUV max analysis in the primary tumour because of the absence of pathologic sampling of the tumour (n = 4), because of the inability to delineate the primary tumour (n = 1) or because of the pathological diagnosis of a LCNEC in a tumour with low tracer uptake (n = 1), yielding 64 primary tumours (52 TC and 12 AC tumours) available for pathologybased SUV max analysis (see the Consolidated Standards of Reporting Trials (CONSORT) diagram in Additional file 1: Fig. S1). The median SUV max value of all pathologically proven TC tumours was 18.4 (range 0.9-110.2) on SSTR PET/CT and 3.5 (range 1.1-8.8) on [ 18 F]FDG PET/CT (Fig. 1). For AC tumours, the median SUV max value was 3.  No TC tumours were found in the lower right quadrant, which represents high [ 18 F]FDG and low SSTR ligand uptake, with all 3 out of 3 tumours (100%) in this quadrant being AC (Fig. 2). The probability to find an AC in the right upper quadrant and the left lower quadrant was 2/8 (25%) and 2/6 (33.3%), respectively, in line with the pretest probability for a tumour being AC (19/86; 22.1%, Table 1).
Of all the patients that underwent a resection of the primary tumour with concurrent hilar and mediastinal lymph node dissection (N = 63)-both after and prior to the SSTR PET/CT-the diagnosis of N0-disease was made in 47 patients (75%), of N1-disease in 4 patients (6.3%), of N2-disease in 9 patients (14%) and of N3-disease in 3 patients (4.8%). Pathology of hilar and/ or mediastinal lymph node stations was available and could be correlated with SUV max values on SSTR PET/ CT in all 51 patients that underwent a resection of the tumour after the SSTR PET/CT. confidence interval (CI) -0.03 to 0.38; p = 0.10) (Fig. 3). ROC curves of non-paired SUV max values in the 267 hilar and mediastinal lymph node stations of TC and AC were generated for both SSTR PET/CT and [ 18 F]FDG PET/CT (Additional file 1: Fig. S4), showing an AUC of 0.82 for the detection of lymph node metastasis of TC on SSTR PET/CT and an AUC of 0.93 for the detection of lymph node metastasis of AC on [ 18 F]FDG PET/CT. Based on the ROC analysis of the non-paired SUV max values in the 167 nodes of TC on SSTR PET/CT, we derived a maximal Youden's index at SUV max 2.1 using resection specimens as well as biopsies for pathological evaluation, resulting in a sensitivity and specificity for regional lymph node involvement of TC on SSTR PET/CT of 80% and 75%, respectively (Table 2). Interestingly, all pathologically examined regional lymph node stations with an SUV max of 4.0 or more on SSTR PET/CT turned out to be metastatic, yielding a true positive rate of 100% at this SUV max cut-off value.
Twelve lesions suspicious for distant metastatic disease seen on SSTR PET/CT in 10 patients were biopsied (CONSORT in Additional file 1: Fig. S5) with pathological confirmation of metastatic disease in all of these lesions, yielding a positive predictive value (PPV) of 100% in this small sub-cohort of patients with pathological validation (

Discussion
In this second largest series since the introduction of SSTR PET/CT (Table 4), we retrospectively evaluated clinical, pathological and imaging data of 86 patients diagnosed with pulmonary NETs. There was a predominance of TC over AC (and LCNEC) and of female over male patients, consistent with epidemiologic data in the literature concerning these tumour types [5,37,38]. Interestingly, in 2 of the 51 patients that underwent surgical resection after the SSTR PET/CT, the diagnosis of PC was made during screening in the context of increased ACTH secretion, consistent with the recent literature evaluating the role of SSTR PET/CT in the detection of ectopic ACTH-secreting tumours [39,40].
While the European guidelines from the European Society for Medical Oncology (ESMO) and the European Neuroendocrine Tumor Society (ENETS) recommend performing SSTR PET/CT in addition to contrastenhanced CT in the TNM staging of PC, recent Commonwealth and North American guidelines also endorse SSTR PET/CT in the detection of metastatic disease, but suggest only a limited clinical utility of SSTR PET in detecting metastases in patients with a small primary PC [1,2,4]. These guidelines are based on a few small to medium-sized studies that evaluated the role of SSTR PET/CT in the staging of PC, as seen in our literature review in Table 4 [23,[41][42][43]. Together with additional series from 2011 until 2020, all authors observed a high SSTR and low [ 18 F]FDG uptake in TC and vice versa for AC, known as the "flip-flop phenomenon" due to the presence of specific molecular markers in the more benign tumours and loss of neuroendocrine markers with increased glycolytic phenotype in the more aggressive tumours [31]. This highlights the value of dual tracer PET/CT in the preoperative assessment of tumour biology [10,[44][45][46][47]. Our study confirms these findings by demonstrating a significant difference in tumoural SUV max values between TC and AC on SSTR as well as on [ 18 F]FDG PET/CT, underscoring the role of SSTR PET in low grade PC and of [ 18 F]FDG PET/CT in intermediate grade PC (Fig. 1). For this pathology-based analysis, we relied mostly (54/64; 84%) on resection specimens, in accordance with recent guidelines for diagnosis and management of patients with lung neuroendocrine tumours [2]. Our median SUV max values in the tumoural lesion are in line with the values reported in the studies listed  Table 4. Based on the literature and our current findings, we suggest to use SSTR PET as first-line molecular imaging test for biopsy-proven TC, whereas for AC the choice between SSTR PET and [ 18 F]FDG PET could be made based on tumour biology (e.g. if high Ki-67 index or mitotic count, start with [ 18 F]FDG). In case of low tracer avidity, additional imaging with the other tracer can be considered.
Furthermore, this is-to the best of our knowledgethe first study in which SUV max values in hilar and mediastinal lymph node stations on SSTR PET/CT were correlated with nodal involvement on pathologic evaluation. We found an AUC of 0.91 on the ROC curve for the detection of regional lymph node metastases from TC on SSTR PET/CT. Based on the maximal Youden's index of this ROC analysis, an associated sensitivity and specificity of 80% and 75%, respectively, was found. However, a rather high rate of false-positive findings at the SUV max cut-off of 2.1 should be kept in mind when interpreting lymph nodes on SSTR PET/CT, entailing the need to confirm lymph node metastases on SSTR PET/ CT that would render the patient inoperable by biopsy. If an SUV max cut-off value of 4.0 was applied, the true positive rate was 100%. Given the crucial role of complete resection of lymph node metastases as well as the tendency for surgeons to perform minimally invasive (sub) lobar tumour resections with more limited lymph node assessment, SSTR PET/CT could be seen as a noninvasive way to determine N status and to guide lymph node dissection in these tumour types [4,32,38,48,49]. In our series as well, 14/51 patients (27%) who underwent a surgical lymphadenectomy after a staging or screening (in the context of ACTH overproduction) SSTR PET/ CT presented with pathologically proven N + stage (cfr example in Fig. 4). [ 18 F]FDG PET/CT also provides a good diagnostic performance in the detection of regional lymph node metastasis in AC (AUC 0.93); however, these data should be interpreted with caution given the small cohort of 11 lymph nodes evaluated for this more uncommon tumour type. The European Society for Thoracic Surgery (ESTS) performed an electronic survey on the surgical management of PCs in 2012, with responses from 172 institutions worldwide. The responders agreed that, if the primary tumour is resectable and if nuclear imaging suggests N2M0 disease, surgery can be performed with no need for further preoperative invasive staging [1].
Finally, regarding detection of metastatic disease, the additional value of SSTR PET/CT is observed in many publications, especially for the detection of bone   (Table 4) [11,50]. In our study, pathological examination of lesions suspicious for metastases during staging or follow-up SSTR PET/CT was obtained in 12 lesions of 10 patients and was positive for metastasis of PC in all lesions, yielding a positive predictive value (PPV)  of 100% for SSTR PET/CT in this small sub-cohort of patients with pathologically evaluated lesions (Table 3). An illustration of a patient from our series with M0 disease on staging CT, but with the diagnosis of multifocal bone metastases on [ 68 Ga]Ga-DOTATATE PET/CT, is shown in Fig. 5, changing the therapeutic approach from curative-intent surgery to non-curative systemic treatment. Although the bone metastases were not pathologically proven in this patient, the SUV max of 39.6 in the most intense lesion was highly suggestive, and follow-up imaging confirmed the M1 stage. One of the major limitations of this analysis is the retrospective nature and the potential selection bias due to the fact that patients who were referred for an SSTR PET/CT could have a higher probability for relapse during restaging or for metastatic disease during staging. Also the fact that the scans were performed at a single university reference centre may contribute to this selection bias. Furthermore, we used two different [ 68 Ga]Ga-peptides and three different PET/CT cameras. Although the tracers have slightly different binding affinities to SSTR subtypes and the different PET/CT cameras improved in performance over the years, there seems to be no clinically relevant difference in the diagnostic accuracy. We included SSTR scans performed in the context of tumour screening, staging, restaging, and therapy evaluation, representing a heterogenous clinical setting. Given the inclusion of 19 patients during follow-up, a possible influence of previous therapies on the SUV max values cannot be excluded. However, this heterogeneity also provides a cross-section of the indications to perform a SSTR PET/CT and resulted in a total cohort of 86 patients, representing the second largest series of SSTR PET/CT in patients with PC in the literature. This was necessary to obtain a sufficiently large number of lesions for the pathological correlation of regional lymph node The role of PET/CT in the assessment of the tumour biology of PC was confirmed based on a significantly higher SSTR ligand and lower [ 18 F]FDG uptake in TC compared to AC. Moreover, a high sensitivity of 80% of SSTR PET/CT in detecting regional lymph node metastases was found. Finally, SSTR PET/CT has a PPV of 100% in a small sub-cohort of patients with pathologically examined distant metastases involvement as well as for the pathological validation of hematogenous metastases. We acknowledge the possibility of discordance between the nodes examined by the pathologist and the localization of these nodes on the preoperative SSTR PET/CT. Finally, in the minority of cases where no resection specimen was available (10/64 (16%) SSTR PET/CTs for tumoural SUV max analysis and 4/56 (7%) SSTR PET/CTs for nodal SUV max analysis), pathological data from biopsies were also included, which could have led to a slight overdiagnosis of TC that would have been classified as AC after resection.

Conclusion
In this study, the performance of SSTR PET/CT in patients with pulmonary neuroendocrine (carcinoid) tumours was studied in a large series with pathology as gold standard. Our results confirm the important role of PET/CT in the assessment of the tumour biology, based on a significant higher SSTR ligand uptake and lower [ 18 F]FDG uptake in TC compared to AC. Moreover, the assessment of the diagnostic performance of SUV max values in pathologically evaluated hilar and mediastinal lymph node stations revealed a high diagnostic accuracy of SSTR PET/CT for regional lymph node metastases of TC. Finally, SSTR PET/CT has a PPV of 100% in patients with pathologically examined metastatic lesions, albeit in a small sub-cohort. Therefore, our data lend support to the current European guidelines (ESMO and ENETs) that recommend first-line conduct of SSTR PET/CT in the staging and restaging of pulmonary NETs.