The cyclic octapeptide octreotide was the first SS analogue to be used in clinical practice. This compound was initially conjugated with diethylene-triamine-pentaacetic acid (DTPA) and then coupled with various radioisotopes especially ¹¹¹In. The sensitivity of this scintigraphy technique has been reported to be about 80–90 %. Positivity on ¹¹¹In-DTPA-octreotide scintigraphy (octreoscan) not only helps to localize the tumor but also helps to predict the response to octreotide therapy. Octreotide can also be conjugated with the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-N,N=,N,N-tetraacetic acid), resulting in ¹¹¹In 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-lanreotide (¹¹¹In-DOTA-lanreotide) and ¹¹¹In-DOTA-Tyr3-octreotide and enabling its use in the diagnosis, staging, and follow-up of patients with NETs [41]. This technique provides whole-body screening and is associated with radiation exposure comparable to that of other imaging modalities.

Sensitivity of SRS in different tumor types is related to various factors such as type and density of SS receptors expressed by the tumor, target-to-background ratio, and tumor site and the histology. In clinical practice, SRS is mainly used for localizing the primary lesion and for evaluating disease extension, monitoring the effects of treatment, as well as a prognostic parameter in predicting the response to therapy.

In a retrospective analysis of pulmonary carcinoids with ¹¹¹In-octreotide scintigraphy, Yellin et al. [42] reported sensitivity of 90 % for SRS. The specificity was 83 % and the positive and negative predictive values were 83 % and 91 %, respectively. Hervás Benito et al. [43] evaluated the role of octreoscan in three cases of pediatric bronchial carcinoids (one preoperative, two postoperative with residual tumor); uptake was noted in all the three cases, which were later confirmed histologically. In one case the scan was able to differentiate between the tumor and associated atelectasis.

Irrespective of the promising results provided above, octreoscan carries a few but troublesome limitations such as limited spatial resolution, low tumor-to-background ratio which might hamper visualization of smaller lesions, and a high false-positive rates due to uptake in many other tumors, granulomas, and some autoimmune disease, thus reducing its specificity.

MIBG (meta-iodobenzylguanidine) is an analogue of biogenic amine precursor resembling adrenergic neurotransmitter norepinephrine. It is taken up by active sodium and energy-dependent uptake mechanism in the cell membrane of sympathomedullary tissue and is stored in the intracellular granules [44]. This molecule can be labelled with either 123I or 131I, with 123I-labelled molecule having better characteristics such as superior spatial resolution and absence of high-energy beta emissions that are emitted from 131I. On the other hand, 131I-MIBG can be a useful cost-effective option as it is much less expensive compared to 123I-MIBG.

The use of 131I-MIBG for the detection and imaging of neuroendocrine tumors was reported as early as the 1980s, followed by papers about its therapeutic applications. The sensitivity of the MIBG scan for carcinoid tumors is reported to be a little lower than that of the ¹¹¹In-pentetreotide scintigraphy scan; however, a combination of these scans increases the sensitivity to 95 % [45]. MIBG scintigraphy may provide advantages over octreoscan in preoperative localization of tumors, as well as radio-guided surgery of neuroendocrine metastatic lesions, if the involved site is located in proximity to highly octreotide-avid organs such as the kidneys or spleen [46].

Being a technetium-99 m-labelled radiopharmaceutical, this molecule has definitive logistical and imaging advantages over octreoscan and MIBG considering the easy availability of the radionuclide, favorable imaging properties, early imaging time, and lesser exposure to radiation to the patients. The radionuclide 99mTc and the somatostatin analogue Tyr3-octreotide are held together by a bifunctional chelator EDDA/HYNIC, a hydrazinonicotinic acid derivative with ethylenediamine N,N’ diacetic acid (EDDA) acting as a coligand; this renders the molecule highly stable in vivo and in vitro [47]. This radiopharmaceutical has been sporadically used to evaluate solitary pulmonary nodules [48] and large cell neuroendocrine carcinoma [49] with rather disappointing results. It carries a low specificity due to high possibility of uptake in benign findings such as foreign body and suppurative inflammations, hamartomas, and tuberculomas [48].

The utility of ¹⁸F-FDG PET scan depends principally on increased glucose metabolism and so-called metabolic trapping – greater trapping of the agent in the more metabolically active tumor cells than in surrounding tissues [50]. ¹⁸F-FDG PET/CT is one of the most commonly utilized investigations in the field of oncology today. Notwithstanding, the utility of this radiopharmaceutical is somewhat limited in the evaluation of NETs. The FDG uptake in carcinoid tumors is low, due to their low proliferative and metabolic activity and high degree of differentiation [51]. The use of ¹⁸F-FDG PET/CT may be reserved for poorly differentiated neuroendocrine cancers with little or no hormone production and a high proliferative activity (Table 17.3). Also, ¹⁸F-FDG PET/CT appears to show a higher SUVmax values for atypical carcinoids than typical carcinoids [57, 58]. This in turn leads to higher sensitivity for detection of atypical carcinoids compared to typical carcinoids. A disadvantage in using ¹⁸F-FDG is that it may be falsely positive in the inflammatory and infective lesions of lung and lymph nodes [52]. Also, other non-carcinoid tumors which can mimic bronchopulmonary carcinoid (mucoepidermoid carcinoma, adenoid cystic carcinoma, schwannoma, and inflammatory myoblastic tumors) show ¹⁸F-FDG avidity that lowers the specificity of ¹⁸F-FDG PET/CT in the detection of bronchopulmonary NETs [52, 55, 59, 60]. ¹⁸F-FDG has been rarely used in the evaluation of thymic carcinoids; a possible role of the modality may lie while searching for a cause of ectopic Cushing’s syndrome where thymic carcinoids may be identified [61–63].

High levels of SSTR expression are generally detected in lung carcinoids, predominantly subtypes 2, 3, and 5, which has been verified by a multitude of in vitro and in vivo studies [64]. This implies that radiopharmaceuticals which target these receptors can help in the detection of these lesions. This has best been achieved with the help of ⁶⁸Ga-DOTA-conjugated SSA. Three such molecules (DOTANOC, DOTATOC, DOTATATE, all labelled with ⁶⁸Ga) have been developed and extensively studied in assessing their role in the detection of pulmonary carcinoids apart from neuroendocrine tumors at other sites [65, 66]. They offer distinct advantages compared to their SPECT counterparts such as octreoscan in terms of superior spatial resolution and earlier imaging times. The superior spatial resolution invariably leads to higher detection rates compared to octreoscan. They have opened up horizons in terms of understanding the biological behavior of these malignancies. The binding molecular affinities and specificities to the different somatostatin receptor subtypes vary between the three molecules [65]. Hence, although they show similar biological distribution and diagnostic accuracies, one ⁶⁸Ga-DOTA-SSA molecule may show superior tumor-to-background ratios and SUVmax values compared to the other [67].

However, one feature common to the three molecules is their often documented inverse relationship compared with ¹⁸F-FDG in uptake values between typical and atypical carcinoids. Two studies at our department also prove this point satisfactorily. The study by Venkitaraman et al. [55] and Jindal et al. [59] evaluated patients with suspected bronchial carcinoids using ⁶⁸Ga-DOTATOC and ¹⁸F-FDG PET/CT studies. They found that the ratio of SUVmax values of ⁶⁸Ga-DOTATOC to ¹⁸F-FDG PET scans was higher in case of typical carcinoids, while atypical carcinoids showed higher SUVmax for ¹⁸F-FDG (Table 17.4).