The Value of Ga68-DOTATATE PET/CT in Diagnosis and Management of Suspected Pituitary Tumors

Backroud Gallium 68-tetraazacyclododecane-tetraacetic acid-octreotate (Ga-68 ‐ DOTATATE) is a selective somatostatin analogue ligand, which shows increased anity for somatostatin receptor subtype (SSTR) 2 and has been used routinely for imaging neuroendocrine tumors with PET/CT. We investigated the utility of Ga-68 ‐ DOTATATE positron emission tomography/computed tomography (PET/CT) in patients with suspected pituitary pathology. We reviewed imaging for twenty consecutive patients (8 men, 12 women, mean age of 48.2, range: 14-78) with suspected pituitary pathology who were referred for Ga-68-DOTATATE PET-CT. Results Nine patients presented with recurrent Cushing's syndrome following surgical resection of pituitary adenomas due to recurrent Cushing's disease (seven patients) and ectopic ACTH secreting tumor (2 patients). All seven patients with recurrent Cushing's disease showed positive pituitary Ga-68-DOTATATE uptake while both cases of ectopic hormonal secretion had absent pituitary uptake. In 1 of these 2 patients Ga-68-DOTATATE was able to localize the source of ectopic ACTH tumor. Six patients presented de novo with Cushing's due to ectopic ACTH secretion; Ga-68 ‐ DOTATATE PET/CT was able to localize ectopic tumors in six of eight patients (3 lungs, 2 pancreases, 1 mid-gut) There was high uptake Ga-68-DOTATATE in 3 cases of recurrent central hyperthyroidism (SUVmax 6.6-14.3) and 2 cases of prolactinoma (SUVmax 5.5 and 11.3). Conclusion Absent Ga-68-DOTATATE activity in the pituitary fossa is useful in excluding pituitary disease in recurrent Cushing’s. Recurrent pituitary thyrotropinomas and prolactinomas showed moderate to high pituitary activity. In addition, in Cushing’s syndrome Ga-68-DOTATATE is useful for detection of ectopic sources of ACTH production, especially where anatomic imaging is negative.


Introduction
Neuroendocrine tumors (NET) cover a heterogeneous group of tumors, which originate from endocrine glands (pituitary, parathyroid, adrenal medulla) or other endocrine organs like thyroid, pancreas, respiratory and gastrointestinal tissue.
The aim of our study was to evaluate the utility of Ga-68-DOTATATE PET/CT imaging scan in patients with suspected pituitary pathology. Patients were divided into two broad groups; those with ACTH dependent Cushing's syndrome and those with recurrent prolactinomas and thyrotropinomas.
Cushing's syndrome is a hormonal imbalance due to abnormally increased levels of cortisol hormone in blood. Cushing's syndrome is divided into 2 types: ACTH-dependent and ACTH-independent forms. In ACTH-dependent type, there is over-synthesis of ACTH from pituitary adenoma, called Cushing's disease (CD), or ectopic secretion of ACTH from peripheral tumors (9). CD is the most common form of endogenous Cushing's syndrome, accounting for approximately 70% of cases (10)(11). Ectopic ACTH secretion is a cause of approximately 15-20% of ACTH-dependent Cushing's syndrome (12). In the literature, several small case series studies have reported on use of Ga-68-peptide ligands to evaluate ectopic ACTH secreting tumors (13)(14)(15)(16). Prolactinomas are relatively common primary pituitary neoplasm's whereas thyrotropinomas are rare. In both cases, however, there is very limited literature on use of somatostatin receptor imaging in vivo.

Patients
A search of our Institutional database over 5-year period between 2008 and 2013 revealed 20 consecutive patients (8 male, 12 females with mean age 48.2 years (range: 14-78 years)) who underwent Ga-68-DOTATATE PET/CT for evaluation of pituitary pathology.
The indication for Ga-68-DOTATATE PET/CT were: (Table 1) a) Suspected recurrent Cushing's disease following previous surgical resection b) ACTH dependent Cushing syndrome secondary to suspected ectopic ACTH production c) Recurrent central hyperthyroidism d) Recurrent prolactinoma PET/CT acquisition parameters Images were acquired 45-60 min after injection of 120-200 MBq of Ga-68-DOTATATE. Imaging was performed using a dedicated GE Discovery STE camera combining a PET unit and a 16-slice CT unit; whole-body examinations (brain to mid-thigh) were performed with the patient supine. The CT exposure factors for all examinations were 120 kVp and 80 mA in 0.8 s. Maintaining patient position, we performed a whole-body PET emission scan covering an area identical to that covered by CT. PET scans were acquired at a rate of 4 min per bed position, and PET images were reconstructed using CT for attenuation correction. The Ga-68-DOTATATE PET acquisitions were performed in 3 dimensions with a 5-slice overlap between consecutive bed positions. Ga-68-DOTATATE PET images were reconstructed using an orderedsubsets expectation maximization algorithm with 3 iterations and 25 subsets. The CT data for Ga-68-DOTATATE were reconstructed to axial slices 3.75 mm thick with a soft-tissue reconstruction algorithm and 2.5 mm thick with a lung reconstruction algorithm.

Image analysis
The documented clinical reports were used to determine results of Ga-68-DOTATATE PET/CT scans. In addition, scans were retrospectively reviewed to document standardized uptake value (SUVmax) in all lesions.
Histological con rmation of tumor type was available for all patients except for one case where ectopic ACTH source for Cushing syndrome was unknown.
All patients had informed consent, and institutional board ethics approval was received for this retrospective study.

Results
Tumor Overview, histology assessment and Ga-68-DOTATATE uptake is summarized in Table 2. 15 patients had Cushing's syndrome. Of these 15, nine presented with recurrent Cushing's following surgical treatment for Cushing's disease. 6/15 patients presented de novo with ectopic ACTH dependent Cushing's syndrome. In 7/9 patients with recurrent Cushing's syndrome there was recurrent pituitary disease. In 2/9 patient's recurrent Cushing's syndrome was due to ectopic ACTH producing tumor.
The source of ectopic ACTH was due to bronchial carcinoid (3 patients), pancreatic NET's (2 patients) and mid gut NET (1 patient). Of 3 bronchial carcinoid tumors, 2 were typical carcinoid (0.8 and 1.7 cm) and 1 was atypical carcinoid (1.5 cm). In one patient, ectopic source of ACTH production was unknown.
In all seven patients with recurrent Cushing's secondary to recurrent Cushing's disease there was positive uptake of Ga-68-DOTATATE within pituitary (SUVmax 2.3-6.1, mean 4.1). In both cases of recurrent Cushing's due to ectopic ACTH production there was absent uptake of Ga-68-DOTATATE in the pituitary.
Pituitary uptake in those with recurrent pituitary adenomas was less than intense than pituitary uptake seen in patients presenting de novo with ectopic Cushing's (SUVmax 4.8-8.9, mean 6.2).
In one with negative Ga-68-DOTATATE uptake, ectopic source of tumor was not shown on any imaging modality, ectopic tumor ACTH production was diagnosed biochemically and on basis of complete resection of pituitary tissue (shown on MRI) as well absent pituitary Ga-68-DOTATATE activity (Fig.3). In another with pancreatic NET there was negative Ga-68-DOTATATE uptake as well as negative CT and MRI with tumor depicted only on EUS.
In one case with unknown primary site on conventional CT/MRI imaging Ga-68-DOTATATE showed site of primary tumor (in terminal ileum).
Three patients presented with recurrent central hyperthyroidism due to thyroid stimulating hormone (TSH) secreting adenoma following previous surgical resection, with increased TSH and free-thyroid hormone levels, and residual pituitary macro adenomas on MRI (size 13 mm, range 11-15 mm). All patients with recurrent thyrotropinomas showed high tracer uptake (Fig.4) within pituitary (mean SUVmax 9.2, range: 6.7-14.3). Two patients with pituitary adenoma secondary to prolactinoma showed moderate to high Ga-68-DOTATATE uptake in pituitary gland (SUVmax 5.5 and 11.3).

Discussion
Our study suggests that, in selected indications, Ga-68-DOTATATE has a useful role in evaluating patients with suspected pituitary pathology.
Ga-68-DOTATATE activity within the pituitary fossa is a marker for functioning pituitary tissue, a property which can help assess patients with recurrent Cushing's syndrome following resection of corticotrophin secreting pituitary tumors. Positive pituitary uptake indicates the presence of functioning pituitary tissue; in all seven patients with recurrent Cushing's disease there was positive uptake within pituitary although this was less than normal pituitary activity seen in those with Cushing's due to ectopic ACTH secretion.
Our ndings are in keeping with Zhao et al. who showed that Ga-68-DOTATATE had higher uptake in normal remaining pituitary tissue than in recurrent or residual pituitary adenomas (17). In contrast both patients with recurrent Cushing's syndrome due to ectopic ACTH secretion had no uptake within pituitary, in keeping with treated pituitary disease.
The diagnosis of Cushing's disease can be challenging. The best imaging modality, MRI may be normal in up to 40% of patients (18). Inferior petrosal sinus sampling (IPSS) is the gold standard for differentiating between pituitary and non-pituitary sources of corticotrophin, with diagnostic accuracy of 87% (18) but is a highly skilled and invasive technique, requiring placement of catheters in both inferior petrosal sinuses (19). Ga-68-DOTATATE is also useful in localization of ectopic ACTH producing tumors. Ectopic ACTH secretion is an infrequent cause of ACTH-dependent Cushing's syndrome. It often presents a major diagnostic di culty because it is hard to differentiate Cushing's disease from ectopic tumors and is often di cult to localize. Ga-68-DOTATATE could detect ectopic ACTH source in 5/6 patients presenting de novo with ACTH dependent Cushing's and 1/2 patients with treated pituitary Cushing's.
Thyrotropinomas are a rare cause of hyperthyroidism in clinical practice often diagnosed as macro adenomas due to delayed diagnosis. Suppression of TSH secretion is mediated via both SSTR 2 and SSTR 5 subtypes (36). Long acting somatostatin analogue drugs reduce TSH secretion and normalize FT4 and FT3 levels in 90% of patients suffering with pituitary TSH secreting tumors (37). In 25 percent of thyrotropinoma cases there is autonomous secretion of a second pituitary hormone (38). One of our 9 patients with recurrent Cushing's syndrome also had the symptoms of central hyperthyroidism with nal diagnosis of plurihormonal pituitary adenoma with expression of ACTH, FSH and TSH (case 7, Table 2). In a study published by Foppiani et al. all 3 patients with TSH-oma were positive in octreoscan (39).
Despite previous pituitary surgery there was moderate increased Ga-68-DOTATATE uptake in patient with recurrent Cushing's and thyrotropinoma and intense uptake in 3 cases of recurrent thyrotropinomas (Fig.  4). Moderate to high pituitary uptake was also seen in both patients with recurrent prolactinomas.

Conclusion
Ga-68-DOTATATE, with integrated PET/CT, is a useful diagnostic modality for the evaluation of patients with suspected pituitary pathology. Recurrent Cushing's disease is associated with positive pituitary uptake of Ga-68-DOTATATE. Although in these cases it would not be possible to distinguish pathological from physiological uptake, positive Ga-68-DOTATATE is useful as it indicates the presence of functioning pituitary tissue. Absence of pituitary uptake in patients with recurrent Cushing's suggests source of ACTH is ectopic. Moderate to high pituitary tracer uptake of Ga-68-DOTATATE was seen in patients with recurrent thyrotropinomas and prolactinomas indicating Ga-68-DOTATATE may be useful for detection of disease post-surgery.
Ga-68-DOTATATE may be helpful in detecting source of ectopic lesion in Cushing's syndrome particularly in those where CT imaging is negative. Finally, locally aggressive or metastatic pituitary tumors may show Ga-68-DOTATATE uptake and therefore indicate potential for treatment with radio labelled somatostatin receptor analogues such as 177 Lu-DOTATATE.