Dual Tracer PET Imaging (68Ga-DOTATATE and 18F-FDG) Features in Pulmonary Carcinoid: Correlation with Tumor Proliferation Index.

Pulmonary carcinoid tumors are rare group of lung neoplasms representing 1% of all the lung tumors. The typical bronchial carcinoids showed higher and more selective uptake of 68Ga-DOTATATE than of 18F-FDG on PET-CT. The Ki-67(MIB-1), a tumor proliferation index is a prognostic marker in neuroendocrine tumors for estimating tumor progression. Atypical carcinoids have higher Ki-67 index and have an increased propensity to metastasize as compared to typical ones. 68Ga-DOTATATE PET imaging along with Ki-67 can be correlated for better management of patients with neuroendocrine tumors. We describe the dual tracer imaging features in a patient of pulmonary carcinoid with avid 68Ga-DOTATATE and minimal 18FDG (18Flurodeoxyglucose) uptake diagnosed on the basis of imaging and bronchoscopic biopsy and its correlation with tumor proliferation index.

Introduction

Carcinoid tumors are tumors of neuroendocrine origin that are rich in somatostatin receptors and show high uptake of radiotracer on octreotidescintigraphy. 68Gallium (68Ga-tetraazacyclododecanetetraaceticacid-octreotate)-labelledDOTATATE (1,4,7,10-tetraazacyclododecane-NI, NII, NIII, NIIII-tetraacetic acid (D)-Phe1-thy3-octreotate) Positron Emission Tomography-Computed Tomography(PET/CT)could be of great help at initial staging, and during follow-up of these patients, particularly in the subgroup with low Ki-67 index.

Case Report

A 36 year male non-smoker presented to us with complaints of cough with intermittent episodes of streaky haemoptysis over the past 3 months. On general examination his vital parameters were within normal limit. Physical examination revealed signs of right lung lower lobe collapse. His complete haemogram and serum biochemistry were within normal limits. Chest radiograph (posterior-anterior view) showed right middle and lower lobe collapse [Figure 1a]. To delineate exact cause patient was subjected to contrast enhanced computed tomography (CECT) of the thorax, which showed an oval homogenously enhancing soft tissue density with tiny calcification along periphery in right bronchus intermedius causing complete occlusion of right middle and lower lobe. Subsequently patient underwent Fiberoptic bronchoscopy, which revealed a polypoidal mass obstructing the right bronchus intermedius about 2 cm from primary carina, which bled on touch. Bronchoscopic biopsy of the mass was taken and histopathology of mass showed features suggestive of carcinoid tumor with tumor cells expressing CK, synaptophysin and chromogranin, and were positive for AE1/AE3 (perinuclear punctate positivity). Tumor proliferation assessment with MIB1labeling index (KI67) was <2%.

Figure 1

a: Chest radiograph (posterior-anterior view) showing right middle and lower lobe collapse (Figure 1b): Computed Tomography of the thorax showing an oval homogenously enhancing soft tissue density in right bronchus intermedius causing complete occlusion of right middle and lower lobe. (Figure 1c): Whole body F18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). Low FDG uptake (SUVmax-3.5) was noted in an ill-defined lesion in right bronchus intermedius causing luminal narrowing and associated distal collapse (Figure 1d): 68Ga-DOTATATE scan showing intense uptake (SUVmax-50.15) in an ill-defined lesion in right bronchus intermedius causing luminal narrowing and associated distal collapse.

As a part of initial staging Whole body 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging [Figure 1c] as well as 68Ga-DOTATATE scan was done, which showed low FDG uptake (SUVmax-3.5) in an ill-defined lesion in right bronchus intermedius causing luminal narrowing and associated distal collapse without any foci of distant metastasis [Figure 1b,1c]. An intense uptake was noted on 68Ga-DOTATATE PET-CT (SUVmax-50.15) suggestive of high SSTR expression at the site of primary [Figure 1d] as would be expected in a case of typical carcinoid with morphological features similar to those seen in the FDG PET/CT images without evidence of metastasis. Eventually, the patient underwent right lower bilobectomy for removal of the tumor in view of favourable prognosisradio graphically and histopathologically. Histopathology of resected tumor also confirmed well differentiated neuroendocrine (carcinoid) tumor, WHO Grade I.

Discussion

Neuroendocrine tumors (NETs) are rare group of neoplasms arising from nervous and endocrine systems. Carcinoid tumors are of neuroendocrine origin, which is derived from primitive stem cells in gut wall. Carcinoid tumors were first described by Lubarsch in 1888.[1] Carcinoid lung tumors represent about 10% of all carcinoid tumors and comprise nearly 1-6% of all lung tumors. Of all tracheo-bronchial tumors, pulmonary carcinoids are third most frequent in occurrence.[2] The majority of these tumors develop in the major bronchi. About 25% of patients with pulmonary carcinoid tumors are asymptomatic at the time of diagnosis and are found incidentally. Chest radiograph are usually nonspecific for diagnosis. They are most frequently seen on Computed Tomography as, round or oval opacities, with sharp and often notched margins with or without atelectasis, consolidation secondary to pneumonia, and bronchiectasis as a sequelae to obstruction. There are no specific signs to differentiate these tumors from one another, as seen in our case, as oval lesion with associated distal collapse. However, due to the recent availability of positron emitting radioisotope labeled somatostatin analogues to image neuroendocrine tumors, it has raised interests to use this new imaging modality in management of patients with NETs. 68Ga-DOTA-TATE PET/CT has demonstrated superiority in lesion detection compared to FDG (18Flurodeoxyglucose) PET/CT, Octreoscan, MIBG (metaiodobenzylguanidine) scintigraphy, and Magnetic Resonance Imaging.[34]

Typical carcinoid tumors are least biologically aggressive type of pulmonary neuroendocrine tumor of the lung, and are most well differentiated. These tumors characteristically grow slowly and metastasize infrequently as opposed to atypical, which are aggressive in nature and tends to metastasize early. The FDG uptake of these tumors is intermediate between benign and malignant lesions and sometimes may be comparable with benign lesions, which can lead to false-negative results on FDG-PET imaging.[5] 18F-FDG is, therefore, thought to be of limited value in the evaluation and disease staging of these patients.[5] However, the (68Ga-odecanetetraacetic acid-octreotate) Gallium-68 labeled (Ga-68) DOTATATE PET/CT scan is a higher-resolution scan, able to detect well differentiated NETs. Because 68Ga-DOTATATE is a somatostatin receptor PET radioligand, and binds to the somatostatin receptors 2 and 5 of the neuroendocrine tumor cells, it can more effectively detect small tumors compared to conventional gamma camera based octreoscan, and is also sensitive to detect small lymph node metastases as it shows intense uptake in these lesions.[67] Therefore, 68Ga-DOTATATE has shown superiority to 18F-FDG in typical (histologically well differentiated) bronchial carcinoids, as in our case, which showed intense uptake (SUVmax-50.15) in lesion bronchus intermedius associated with adjacent collapse in 68Ga-DOTATATE as compared to low uptake in same area in 18FDG-PET(SUVmax-3.5). It also helps to correctly delineate endobronchial tumor from adjacent atelectasis, which cannot be at times well differentiated on 18F-FDG.[8] The avidity of 68Ga-DOTATATE may be useful to identify sites of possible differentiation at initial staging as well as during follow-up period.[8] Hence, 68Ga-DOTATATE PET/CT has been found to be useful not only as a part of initial staging in cases of primary bronchial carcinoid, but also for the staging and evaluation of recurrent/metastatic pulmonary neuroendocrine tumors.

The Ki-67 index is one of the most useful discriminators of tumor grade. It is a prognostic marker in neuroendocrine tumors and for the estimation of tumor progression.[9] MIB-1 is used in clinical applications to determine the Ki-67 labeling index, having advantage of being estimated on formalin-fixed sections. Ki-67, a nuclear antigen, is a cell cycle associated protein. Mitoses ≥2 is a powerful predictor of metastasis.[10] There is a higher Ki-67 index in atypical carcinoids and also higher chances of metastasis, which significantly correlates with histological grading and proliferative activity. The patients with low Ki-67 index on histopathology may have favourable outcome as seen with typical carcinoids. Ki-67(MIB-1) and 68Ga-DOTATATE PET imaging are a useful adjunct for predicting metastasis (shows intense uptake) and for initiating adjuvant multimodal therapy in lung carcinoid tumors. In our case there was a high uptake of tumor on 68Ga-DOTATATE PET with low Ki-67(MIB-1) index (<2%) without evidence of metastasis, as is usually seen with typical carcinoid having favorable outcome (with limited resection like tumor removal) and without requiring any adjuvant multimodal therapy. Pulmonary carcinoids have significantly better prognosis compared to the other pulmonary malignancies with a multitude of resectional surgeries available for definitive management. Our case illustrates the fact that 68Ga-DOTATATE PET/CT should be the imaging modality of choice, in cases of suspected carcinoid tumors, to have a better morphological delineation and to assess any metastases.

Thus, we conclude that 68Ga-DOTATATE PET imaging coupled with tumor proliferation index can be correlated for better management of the patients with neuroendocrine tumor. Particularly, carcinoid and Ki-67 index should be routinely evaluated in pulmonary carcinoid tumors along with the 68Ga-DOTATATE PET scan.

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Conflicts of interest

There are no conflicts of interest.