J Gastrointest Surg (2016) 20:180–188 DOI 10.1007/s11605-015-2953-6
2015 SSAT PLENARY PRESENTATION
Role of Staging in Patients with Small Intestinal Neuroendocrine Tumours Ashley Kieran Clift 1 & Omar Faiz 2 & Adil Al-Nahhas 3 & Andreas Bockisch 4 & Marc Olaf Liedke 5 & Erik Schloericke 5 & Harpreet Wasan 1 & John Martin 6 & Paul Ziprin 1 & Krishna Moorthy 1 & Andrea Frilling 1
Received: 15 May 2015 / Accepted: 14 September 2015 / Published online: 22 Septem ber 2015 # 2015 The Society for Surgery of the Alimentary Tract
Abstract Small bowel neuroendocrine tumours are the commonest malignancy arising in the small intestine and have substantially increased in incidence in recent decades. Patients with small bowel neuroendocrine tumours commonly develop lymph node and/or distant metastases. Here, we examine the role of staging in 84 surgically treated patients with small bowel neuroendocrine tumours, comparing diagnostic information yielded from morphological, functional and endoscopic modalities. Furthermore, we correlate pre-operative staging with intra-operative findings in a sub-cohort of 20 patients. The vast majority of patients had been histologically confirmed to have low-grade (Ki-67 <2 %) disease; however, lymph node and distant metastases were observed in 74 (88.1 %) and 51 (60.7 %) of patients at presentation, respectively. Liver metastases were evident in 48 (57.1 %) patients, with solely peritoneal and bone metastases observed in 2 (2.4 %) and 1 (1.2 %) patients, respectively. Forty patients (47.6 %) received multimodal treatment. In our sub-cohort analysis, pre-operative imaging understaged disease in 14/20 (70 %) when compared with intra-operative findings. In patients with multifocal primary tumours and miliary liver metastases, no imaging modality was able to detect entire disease spread. Overall, presently available imaging modalities heavily underestimate disease stage, with meticulous intra-operative abdominal examination being superior to any imaging technology. Multimodal treatment has an important role in prolonging survival. Keywords Small bowel . Neuroendocrinetumours . Staging . Surgery
This paper was presented as an oral presentation at Digestive Disease Week, 18th of May 2015, Washington, D.C. (SSAT Plenary Session). * Andrea Frilling
[email protected] 1
Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK
2
Department of Surgery, St. Mark’s Hospital, London, UK
3
Department of Nuclear Medicine, Imperial College London, London, UK
4
Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
5
Department of Surgery, Westkuesten Klinikum Heide, Heide, Germany
6
Department of Gastroenterology, Imperial College London, London, UK
Introduction Small bowel (SB) neuroendocrine tumours (NETs) are increasingly raising attention in clinical practice. Representing the commonest small bowel malignancy1,2 and also the most frequent neuroendocrine neoplasm of the gastro-enteropancreatic tract,3 SB NETs are also steadily increasing in incidence, with approximately three- to fivefold increases over the past three decades evident in analyses of several registries.3–8 Gender disparity has been demonstrated in this evolving epidemiology; a 2.7-fold increased incidence of SB NET in males compared to a 1.8-fold increase in females was reported in an analysis of National Cancer Registry data for England.8 In 20–30 % of patients, SB NETs occur as multicentric lesions which are distinct from solitary tumours at clinicopathological and molecular levels.9,10 Compared to
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those with solitary primary lesions, individuals with multiple tumours are often younger, more frequently exhibit the carcinoid syndrome and have a poorer prognosis.11 Notably, an association between SB NETs and non-neuroendocrine second primary malignant neoplasms has been reported in up to 55 % of cases depending on the study.12 Despite historical, oft-promulgated views that they are relatively indolent neoplasms, SB NETs have a preponderance to develop loco-regional and/or distant metastases (particularly to the liver). Depending on the technology used, lymph node metastases and liver metastases can be detected in up to 90 and 60–80 % of patients, respectively.13–17 The diagnostic armamentarium for SB NETs and their metastases encompasses various imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI),18 intravenous contrast-enhanced ultrasound (CEUS), positron emission tomography (PET), somatostatin receptor-targeted imaging,19,20 CT or MR enterography,21 standard endoscopy, doubleballoon enteroscopy22 and video capsule endoscopy (VCE).23 Surgical elimination of the primary tumour including locoregional and distant metastases plays a key role in the treatment of patients with SB NET. Even in patients with advanced tumour stage, 5- and 10-year survival rates from diagnosis of 67–87 %16,17,24–26 and 50–77 %,17,24 respectively, have been reported. The aim of this study was to investigate the role of staging in patients with SB NET, its impact on treatment strategies and its accuracy compared with findings at laparotomy.
Methods Patients with SB NET seen at three institutions (Imperial College Healthcare NHS Trust, London, UK; University Hospital, Essen, Germany; and University Hospital, Hamburg, Germany) by the same clinician (A.F.) during the period April 1998 to February 2015 were included in this study. Imperial College Healthcare NHS Trust has the status of a European Neuroendocrine Tumor Society (ENETS) Centre of Excellence. Data were extracted from a prospectively maintained database for neuroendocrine neoplasms. As all the three aforementioned institutions were tertiary referral centres for NET, patients were frequently referred for further, specialist management following a primary diagnosis elsewhere. Staging of disease was undertaken either in treatment-naïve patients or in the form of re-staging during the patient journey. All included patients underwent surgery at some stage during the course of their disease. Individuals with neuroendocrine tumour disease not amenable for resection underwent multimodal treatment which could incorporate peptide receptor radionuclide therapy (PRRT), liver-directed percutaneous or angiographic ablation, somatostatin analogue therapy or, in the case of G3 tumours, cytotoxic chemotherapy.
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In all the patients, the diagnosis of a neuroendocrine tumour was confirmed pathologically with conventional histology and immunohistochemistry for NET-specific markers using tissue derived from samples obtained either at biopsy and/or during surgical exploration. Biochemical tests included assessment of chromogranin A and B, gut hormones and 5hydroxyindoleacetic acid (5-HIAA) in 24 h urine, the results of which are not presented here. Tumour staging and grading were in accordance with the ENETS consensus classification systems.27 The selection of diagnostic procedures including CT, MRI, CEUS, somatostatin receptor-targeted imaging and endoscopic procedures was tailored to individual clinical situations, with morphological imaging using standard techniques (CT/MRI) as the initial method. During the very early phase of the study period, patients with G1 or G2 tumours underwent 111In-octreotide scintigraphy for functional imaging, 28 whereas since 2000, 68 Ga-DOTATOC or 68 GaDOTATATE PET/CT was utilised as the standard functional imaging modality in such patients. For G3 lesions, 18F-FDG (fluorodeoxyglucose) PET/CT was used. Only results of 68GaDOTATOC or 68Ga-DOTATATE PET/CT were analysed for the purpose of this study, the techniques of which have been reported previously by our group.29,30 Selected patients with metastatic NET where the primary tumour could not be identified on standard imaging underwent VCE. Results obtained from these diagnostic procedures were compared with regards to the staging information they each yielded. Additionally, we examined a sub-group of 20 patients who all underwent surgery as the initial treatment strategy for their disease during the last 36 months of the study period, and compared the results of their pre-operative staging with intraoperative findings. The information regarding patient status at last follow-up was obtained in March 2015. All statistical analyses were executed using IBM SPSS™ software (version 22), with the significance level set at p<0.05 and all p values being two-sided. The unpaired t test or Welch’s t test was used in the comparison of means, whilst associations between categorical variables were assessed using Pearson’s chi-square or Fisher’s exact tests. Kaplan-Meier methodology was used to construct survival curves, which were compared with the Mantel-Cox log-rank test.
Results Eighty-four patients were included, basic demographics and tumour characteristics of whom are displayed in Table 1. Forty-six patients (54 %) were male and 38 (45 %) were female, with a mean age of 59.6 years. Tumour grading was available for 78/84 (92.8 %) of patients, the vast majority of which harboured G1 NET. Twelve patients (14.3 %) had multifocal primary tumours (Fig. 1); in these patients, the number
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182 Table 1
Demographic and clinical characteristics of the study cohort
Parameter
N (%)
Total number of patients Mean age (years) (range)
84 59.6 (32 to 88)
Gender Male
46 (54.8)
Female Tumour functionality
38 (45.2)
Functioning Non-functioning
27 (32.1) 57 (67.9)
Tumour grade G1 G2 G3 Tumour stagea T1–4N0M0 T1–4N1M0 T1–4N0M1 T1–4N1M1
65/78 (83.3) 11/78 (14.1) 2/78 (2.6) 9 (10.7) 24 (28.6) 1 (1.2) 50 (59.5)
a
According to imaging (tumour grade according to ENETS classification27)
of lesions ranged from 3 to 29 with a median size of the largest tumour of 0.8 cm (range 0.3–2.5 cm). All 84 patients underwent staging with the above procedures. Despite the overwhelming majority of our patients harbouring low-grade NET, only 9 (10.7 %) showed no degree of metastasis of the primary tumour, corresponding to ENETS stages I–IIIA.27 Furthermore, 74 (88.1 %) demonstrated any degree of lymph node involvement and 51 (60.7 %) displayed distant metastatic spread (ENETS stages IIIB and IV, respectively). Forty-eight patients (57.1 %) were observed to harbour hepatic metastases; these included 2 patients with
Fig. 1 Intra-operative finding in a patient with a multifocal SB NET with a total of 29 deposits scattered through the ileum. There were also bilobar liver metastases and a bulk of mesenteric lymph node metastases
concomitant liver and bone lesions and 1 patient with coexistent hepatic and peritoneal metastases. Solely peritoneal and bone metastases were observed in 2 (2.4 %) and 1 (1.2 %) patients, respectively. No patients were found to have pulmonary metastases. Although the patients from ICHNT were significantly older than those from Germany at initial presentation (means 61.75 vs. 56.16 years; t′=4.254, p=0.042), the two sub-sets were not significantly different with regards to the incidence of nodal, distant or hepatic metastasis (p=0.083, p=0.313 and p= 0.557, respectively). No significant associations were observed between patient age nor gender and the incidence of lymph node metastases (p=0.591 and p=0.747, respectively), although this is unsurprising, given the high rate of nodal involvement. Furthermore, age was not a significant risk factor for distant or hepatic metastases (p=0.644 vs. p=0.593), nor was gender (p=0.677 vs. p=0.311). The incidence of lymph node and distant metastases was not significantly different between tumour grades (p=0.342 and p=0.929, respectively), but this may be attributable to the very low number of patients with G3 tumours. Eighty patients underwent 68Ga-DOTATOC or 68GaDOTATATE PET/CT either at the initial presentation or during their disease course. Pathologically increased radiotracer uptake was observed in at least one lesion in every patient, yielding a 100 % sensitivity on a patient basis which confirms previous reports.29 On comparing results of standard morphological (CT, MRI, CEUS) and somatostatin receptor-targeted imaging, it became apparent that such morphological modalities considerably underestimated the stage of disease and 68GaDOTATOC or 68Ga-DOTATATE PET/CT demonstrated additional lesion sites and/or additional lesions within the same site (e.g. liver or skeletal system) in 51/80 (63.8 %) patients (Figs. 2 and 3). However, somatostatin receptor-targeted imaging had intrinsic limitations in detecting sub-centimetre lesions in the liver and small bowel. Indeed, 68Ga-DOTATATE PET/CT failed to identify lesions <10 mm in size in all of the 7 patients with multifocal SB NET undergoing functional imaging prior to resection of the primary tumour. Furthermore, we undertook a sub-cohort analysis of 20 recent surgically treated patients to correlate the results of pre-operative staging with multiple diagnostic modalities and intra-operative findings (Table 2). Ultimately, seven of these patients were found to have multifocal primary tumours. However, no diagnostic modality was able to identify this, with tumour multi-centricity demonstrated only at laparotomy by meticulous bowel palpation. Additionally, 4/20 patients had hepatic metastases, many of which were less than 10 mm in size, but no diagnostic modality was able to identify these pre-operatively, including 68Ga-DOTATATE PET/CT. Overall, pre-operative disease staging underestimated the true disease burden in 14/20 (70 %) of patients as discovered by the surgeon intra-operatively.
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Primary tumour
Physiological uptake in bowel loops Bone metastasis
Fig. 2 68Ga-DOTATATE PET/CT demonstrating bifocal pathological uptake. It corresponds to the primary tumour in the right iliac fossa and a solitary bony metastasis. Faint uptake in the left iliac fossa represents physiological tracer uptake in the small bowel loops
Forty patients (47.6 %) were offered multimodal treatment during the course of their disease, which included combinations of surgery with somatostatin analogues, PRRT and liverdirected therapies such as trans-arterial chemoembolisation or selective internal radiotherapy. Transplantation procedures were utilised in 4 highly selected patients; 3 underwent orthotopic liver transplantation,31 and 1 with a multifocal SB NET and extensive, non-resectable mesenteric lymph node metastases (level IV) received a modified liver-free multivisceral transplant.32 Mean follow-up length for the cohort was 76.13 months (6.34 years, range 1 to 251 months, with overall survival from
Surgical clips
Lymph node metastasis
Fig. 3 68Ga-DOTATATE PET/CT showing presence of surgical clips following laparoscopic segmental ileal resection for a SB NET. A lymph node metastasis corresponding to an area of increased uptake close to the site of the primary tumour remained overlooked at the initial surgery. The patient underwent consecutive laparotomy and lymphadenectomy
diagnosis shown in Fig. 4). Kaplan-Meier methodology estimated a mean survival time of 164.25 months (13.69 years, 95 % confidence interval (CI) 137.1 to 191.4 months). Overall (absolute) survival at 5 and 10 years for the entire cohort was 89 and 59 %, respectively. Survival was compared between patients with and without hepatic metastases at presentation, and the mean survival was 141.21 months (95 % CI 109.9 to 172.5) vs. 189 months (146.7 to 232.1), respectively (Fig. 5). In patients without liver metastases, 5-year overall survival was 100 % (95 % CI 100–100), which is significantly higher than that for patients with liver metastases (84, 95 % CI 72.2 to 95.8). Ten-year overall survival rates in those without and with liver metastases was 79 % (95 % CI 57.4 to 100) and 48 % (95 % CI 28.4 to 67.6), respectively, yet this was not significantly different. When comparing the overall KaplanMeier survival curves for both sets, a trend towards favourable survival was seen in those without hepatic metastasis, yet this was not significantly different (Mantel-Cox χ2 =2.671, p=0.1). However, patients diagnosed with distant metastases to any site at presentation had a significantly lower (absolute) overall survival than those who did not (Mantel-Cox χ2 =4.504, p=0.034) (Fig. 6).
Discussion With this study, we have demonstrated that (a) virtually all patients with SB NET have lymph node metastases and more than half have distant metastases, (b) currently available staging modalities heavily underestimate the stage of disease, (c) intraoperative abdominal exploration including meticulous bowel palpation is superior to any pre-operative staging and (d) multimodal treatment concepts including surgery, targeted therapies and liver-directed interventions are contributing to prolonged long-term survival when compared to historical cohorts. In contrast to pancreatic neuroendocrine neoplasms where G1 lesions constitute approximately half of all cases,33 more than two thirds of SB NET are G1 tumours.17,34,35 Although characterised as well-differentiated tumours possessing low proliferative activity, virtually all of these tumours metastasise to mesenteric lymph nodes17,36,37 and frequently to distant sites. Gonzales et al. have most recently demonstrated the prognostic relevance of mesenteric tumour deposits in SB NET, which they defined as discrete mesenteric tumour nodules >1 mm in size with an irregular growth profile and close proximity to large blood vessels and nerves.35 In this study, mesenteric tumour deposits which could be distinguished from mesenteric lymph nodes were observed in 60 % of patients and contributed towards poorer survival outcomes. Accurate assessment of the extent of metastatic disease foci is strongly dependent upon which diagnostic modalities are employed for tumour staging; various studies including some from our own group have shown that somatostatin receptor-
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184 Table 2
Comparison of pre-operative findings with different staging modalities against intra-operative findings in our sub-cohort of 20 patients
Patient
CT/MRI
68
Ga-DOTATATE PET/CT
VCE
Colonoscopy
Enteroscopy
Additional intra-operative findingsa
T
N
M
T
N
M
T
T
T
T
N
M
1 2
0 0
0 0
1 1
1 0
0 0
1 1
NP NP
1 0
NP NP
0 1m
1 0
1m 1m
3 4 5
0 1 0
0 0 0
0 0 0
0
0
1
0
0 NP 0
1 NP 1
1 NP 1
NP NP NP
0 0 0
0 0 1
0 0 0
6 7
0 0
0 0
0 1
1 0
0 0
0 1
NP 1
1 1
NP NP
0 0
1 1
0 1m
8 9
0 1
1 0
0 0
0 1
1 0
0 0
NP NP
0 1
NP NP
1m 0
0 1
0 0
10 11
1 1
0 1
0 1
0 0
1 1
0 1
NP NP
0 NP
NP NP
0 0
1 0
0 0
12 13
1 0
0 1
0 0
1 1
0 1
14
1
1
0
b
0 0 NP
NP NP NP
0 1 NP
NP NP NP
0 0 0
0 0 0
0 0 0
15
1
1
1
0
1
1
1
0
NP
1m
0
1m
16
0
1
0
0
1
0
1
0
NP
1m
1m
0
17
1
0
0
1
0
0
NP
1
NP
0
1
0
18
0
0
0
1
1
0
NP
0
NP
1m
0
0
19
1
0
0
1
0
0
NP
NP
1
1m
1
0
20
1
0
0
1
0
0
1
0
NP
1m
0
0
b
0 corresponds to a negative finding, and 1 represents a positive finding NP not performed, m multifocal or multiple, T primary tumour, N lymph node metastases, M distant metastases, T1m multifocal primary tumour, N1m multiple nodal metastases, M1m multiple distant metastases a
Including sonography of the liver
b
Patient had emergency surgery
Fig. 4 Overall survival of the patients with a small bowel NET
Fig. 5 Overall survival stratified by the presence of liver metastases. LM liver metastases
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Fig. 6 Overall survival stratified by the presence of any distant metastases
based PET/CT technology is clearly superior to standard cross-sectional imaging in the detection of G1 and G2 NET in many aspects and bears influence on therapeutic strategies.29,38,39 In our experience in patients with neuroendocrine liver metastases considered for liver surgery, 68GaDOTATOC PET/CT identified primary tumour recurrence, lymph node metastases, bone metastases and lung metastases more frequently than standard imaging. In contrast, the sensitivities of 68Ga-DOTATOC PET/CT and standard imaging were comparable for the detection of liver metastases and primary tumour site.29 In a study of patients with metastasised NET reported by Schraml et al., overall lesion-based detection rates were comparable for 68Ga-DOTATOC PET/CT and whole-body MRI, although PET/CT was superior to wholebody MRI in the detection of lymph node and pulmonary lesions and inferior in the identification of liver and skeletal metastases.40 For patients with pathologically proven NET negative on somatostatin receptor imaging or higher-grade tumours, 1 8 F-FDG PET/CT may provide valuable information.41 Over the last two decades, molecular imaging has evolved as a standard of care in the diagnosis of NET with a pivotal role in the decision-making process for the selection and planning of treatment.42,43 However, the Achilles’ heel of any available imaging technology is the detection of microscopic disease; this must be borne in mind when extrapolating treatment plans from imaging results. This was poignantly shown in the study of Elias et al. comparing pre-operative imaging with meticulous thinslice histopathological examination, which demonstrated that fewer than half of neuroendocrine liver metastases were detected on the former.44 Of note, the size of the smallest metastases was ≤2 mm in 54 % of patients.
185
These limitations of clinical staging become further evident upon comparison of pre-operative staging results with intraoperative exploration findings. In this series, we found that the former underestimated macroscopic disease extent in 65 % of surgical patients. Most disappointingly, miliary liver metastases and smaller foci of primary lesions escaped preoperative detection entirely. Degrees of overlap between larger and smaller metastases and high physiological uptake of tracer by normal liver parenchyma and, sometimes too, by small bowel loops may all be contributing factors to these false negatives and, potentially also, to false positives on PET/CT imaging. A similar experience was reported by Chambers et al. who retrospectively compared results of pre-operative imaging in patients undergoing abdominal surgery for SB NET.36 Mesenteric lymph node metastases were observed on imaging and intra-operatively in 73 and 88 %, respectively. Peritoneal disease was seen in 6 % of patients on imaging vs. in 25 % at laparotomy, with the authors concluding that staging for SB NET is most accurately performed at surgery. The staging limitations with regards to multi-centric primary tumours were not addressed by this study, but it has been done so in others. Imperiale et al. described a patient with a multifocal ileal neuroendocrine tumour in whom pre-operative staging (including VCE and 18F-FDOPA PET/CT) detected three tumour foci, whilst five additional tumours were found by visual inspection and palpation, and four further tumours were evident at pathological examination.45 Tumour multi-centricity was identified as a risk factor for disease relapse after radical surgery in a series of 100 patients with ileal NET.46 Intriguingly, these results suggest that the laparoscopic approach in surgical management of SB NET should be taken cautiously. In the only published larger series on laparoscopic SB NET resection reported by Figueiredo et al., surgery was carried out laparoscopically in 16 % of their patients.47 The number of patients with multiple primary tumours and the number of harvested lymph nodes were comparable between groups. In our series, two patients required re-operation following an initial laparoscopic approach elsewhere: in one, a multifocal tumour was overlooked, and in another, not all mesenteric lymph node metastases were resected at first surgery (Fig. 3). Historically, the survival of patients with metastatic SB NET has been considered as poor. Indeed, in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) cancer 17 registry encompassing the time period 1973–2007, the 5-year survival for SB NET of any tumour stage was 68.1 %3 vs. 43.2–46.4 % in those with distant metastases.48 Comparable results have been reported from a European cancer registry with a 5-year survival rate of 60.3 %.49 When patients are delineated according to geographical areas, 5-year survival was 64.2, 62, 55.1 and 58.2 % in Western continental Europe, Northern Europe, Eastern Europe and the UK, respectively. Following an aggressive surgical policy and implementation of a multimodal treatment
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approach, more encouraging survival data have been demonstrated in recent series.50,51 The Uppsala group showed in a large cohort of 603 consecutive patients that lymph node metastases, liver metastases and peritoneal metastases are independent prognostic factors and also that resection of the primary tumour with mesenteric lymph node metastases contributes towards a better survival.17 Boudreaux et al. reported 5- and 10year survival from diagnosis of 87 and 77 %, respectively, in a cohort of 189 patients who underwent a total of 229 cytoreductive resections.24 Another, multi-centric study of UK patients with midgut NET metastatic to the liver demonstrated a 5-year survival of 56 % after diagnosis of liver metastases.16 Resection of the primary tumour and liver metastases, treatment with somatostatin analogues and PRRT were factors associated with improved prognosis. Our results are in line with these experiences: by following an aggressive multimodal approach, we were able to attain a 5-year survival of 89 % in a cohort of patients of whom 90 % had metastasised tumours. Upon analysis of the prognostic impact of liver metastases, 5-year survival from diagnosis was 100 % in patients with no hepatic metastases compared to 84 % in the case of liver involvement. Somatostatin analogues are a key adjunct to surgical therapy in the multimodal treatment concept of SB NET, arguably a contributor being the anti-proliferative efficacy of such drugs as shown in two prospective randomised trials demonstrating improved progression-free survival (PFS) in the treatment arms when compared to placebo.52,53 Most recently, the efficacy of PRRT with 177Lu-octreotate was studied specifically in patients with advanced SB NET. Sabet et al. reported disease control in 91.8 % of patients, with a median PFS and overall survival of 33 and 61 months, respectively.54 It remains to be proven in the context of randomised clinical trials if these somatostatin receptor-targeted therapies bear an impact on recurrence-free survival of SB NET patients in an adjuvant setting. Whilst currently available standard clinical staging technology for SB NET—including biochemical tumour markers, morphologic imaging, functional imaging and various endoscopic techniques—appears to have reached its limits, novel approaches in disease-specific molecular staging have recently been reported.55 For example, a PCR-based blood gene transcript analysis was shown to correlate with the results of 68 Ga-DOTA-somatostatin analogue PET/CT and to predict disease status in patients with NET.56 Such blood transcript analyses were demonstrated in a case report to be more sensitive than chromogranin A (the classical serum tumour marker for NET) and that the elevation of gene transcripts was measurable prior to evidence of disease recurrence on imaging.57
techniques has a central role in the management of patient with small bowel neuroendocrine tumours. Nevertheless, staging underestimates the disease burden in a substantial number of cases. Intra-operative visual exploration and visceral palpation is superior to any staging modality available in current clinical practice. Since the vast majority of patients present in a metastasised stage, multimodal treatment concepts need to be considered in order to improve prognosis. Novel molecular staging technology may enhance present staging approaches and monitoring of disease throughout the patient journey.
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Primary Discussant Rasa Zarnegar, M.D. (New York, NY) Excellent study and commend the authors and presenting their work. It is a great database with a large selection of patients with a rare disorder so your work will have impact on the future diagnostic and management algorithms of patients with neuroendocrine disorders. However, I feel that the study indicates that most imaging modalities including 68Ga-
DOTATOC or 68Ga-DOTATATE positron emission tomography (PET)/ CT fail to successfully identify a large proportion of tumour metastasis or multifocal disease and the best diagnostic and therapeutic test is surgical exploration. In your 20 patients that were followed surgically, it appears that pre-operative endoscopy/colonoscopy localised the primary tumour and CT scan was able to identify 100 % of patients with metastasis; therefore 1. How do you envision 68Ga-DOTATATE PET/CT should guide clinicians in the peri-operative setting? 2. What were the surgical findings in the other 60 patients? 3. What is your follow-up strategy in patients as far as imaging is given the relative weakness in staging?
Closing Discussant Dr. Frilling We would like to thank Dr. Zarnegar for his very kind overall assessment of the quality of our work and for his insightful comments. Our responses to his comments are as follows: 1. How do you envision 68Ga-DOTATATE PET/CT should guide clinicians in the pre-operative setting? Imaging with radiolabeled somatostatin analogues has a pivotal role in the diagnostic algorithm of G1 and G2 neuroendocrine tumours and should be performed prior to any treatment decision. Ideally, PET technology utilising gallium-68 conjugated to chelators such as DOTA should be available. In comparison to octreoscan (111In-DTPA-octreotide), it has a two- to threefold higher spatial resolution and a tenfold higher binding affinity to somatostatin receptor subtype 2. 68Ga-DOTATATE, 68GaDOTATOC or 68Ga-DOTANOC PET/CT or PET/MRI not only detects more lesions than standard imaging but also impacts treatment decisions. In a series of 52 patients with neuroendocrine liver metastases referred to us for liver resection, results of 68Ga-DOTATOC PET/CT imaging altered our initial treatment decisions in nearly 60 % of patients. Of them, every second patient was considered as unsuitable for surgical therapy due to metastatic deposits or primary tumour recurrence hitherto unidentified on standard CT and/or MRI imaging. In our experience, 68Ga-DOTA PET/ CT is particularly helpful in the detection of lymph node metastases, skeletal metastases or local recurrence of primary tumours localised in the rectum or lung. 2. What were the surgical findings in the other 60 patients? We agree with Dr. Zarnegar’s opinion that imaging modalities including somatostatin receptor-based PET/CT understage disease in a substantial number of patients with neuroendocrine tumours. By comparing the results of different pre-operative staging modalities with intra-operative findings assessed by the surgeon in a sub-group of 20 patients, we have shown that imaging underestimated the disease stage in 70 %. We intentionally restricted this analysis to a sub-group of patients who were treated in the last period of our study in order to facilitate assessment of the most recently available technology. We presume that the results in the remaining group of patients would most likely be similar, albeit potentially biased by the limitations of the then-available technology. 3. What is your follow-up strategy in patients as far as imaging is given the relative weakness in staging? Our follow-up strategy depends on the primary tumour site and the tumour grade. It encompasses assessment of clinical symptoms, biochemical tumour markers, morphologic imaging, functional imaging and various endoscopic techniques. Whilst diffusion-weighted MRI has a high sensitivity in detection of hepatic metastases, 68GaDOTA PET/CT is particularly effective in the identification of extrahepatic disease. Overall, none of these tools are ideal and there is significant unmet need for novel technology allowing early identification of residual or recurrent disease.
