We report our initial experience with Met-PET/MRCR in 13 patients with microprolactinomas and dopamine agonist intolerance or resistance, in whom standard clinical MRI was considered indeterminate or negative. In all 13 cases, Met-PET demonstrated a focus of increased (often intense) tracer uptake (Figs. 2–4 and Supplementary Fig. 1). In some instances, this correlated with an area that had been identified on MRI as possibly in keeping with an adenoma, but in other subjects Met-PET did not support MRI findings and/or revealed a previously undisclosed abnormality (Table 1; Figs. 1–4 and Supplementary Fig. 1). In all five patients who proceeded to surgery, complete and sustained biochemical remission was achieved, often for the first time in many years, with histology confirming a lactotroph adenoma in four cases. In the fifth patient, an obvious abnormality was found at surgery at the site identified on Met-PET, but histology was not confirmatory of a prolactinoma; however, this likely reflected a small tumor with total resection as evidenced by restoration and maintenance of normal serum prolactin following surgery – analogous to surgical/histological findings in some corticotroph tumors. In the patient with recurrent hyperprolactinemia following previous TSS (Case 10), in whom recurrent tumor was localized within the left cavernous sinus, SRS was followed by a progressive fall in serum prolactin to near normal levels (1.4 ⋅ULN) (Table 1 and Figs. 1 and 4). Importantly, in all patients undergoing surgery, normal pituitary function was maintained or restored, and there were no other surgical complications.
Traditonally, dopamine agonist therapy has been considered the cornerstone of management of patients with prolactinoma [5,49]. In particular, cabergoline is recommended as it has superior efficacy in achieving normoprolactinaemia and tumour shrinkage, when compared with bromocriptine and quinagolide. However, two important factors merit consideration before embarking on medical therapy: (i) the potential need for long-term treatment and (ii) possible adverse effects of dopamine agonist therapy. With respect to treatment duration, two recent systematic reviews concluded that following withdrawal of medical therapy, which is usually undertaken after two years of treatment, only approximately one-third of patients will achieve sustained remission [50,51]. As a result, many patients require long-term (even > 10 years) treatment . Although dopamine agonists are generally considered safe, a longer duration of treatment means that there is an extended exposure window in which the patient may experience side effects, and which may have particular relevance, for example, when considering the risk of cardiac valvular fibrosis [8, 10]. In addition, in recent years, concerns have surfaced regarding the possible adverse psychological effects, and in particular the previously unrecognized high prevalence of impulse control disorders (ICDs), in those treated with dopamine agonists [11–15,52], which were not fully appreciated when earlier guidelines were published . Accordingly, recent guidelines acknowledge that surgery can be considered as a first line treatment option for microprolactinomas where complete resection is deemed possible following specialist neurosurgical evaluation .
In support of this, several groups have reported on the effectiveness and safety of prolactinoma surgery [21–24,29,54–62]: after a follow-up of 13.5 to 102 months, overall remission rates ranged from 26–92%, with most estimates around 70%, although not all studies have provided clarity on whether patients required ongoing dopamine agonist therapy to achieve postoperative remission. Not surprisingly, most studies have reported higher remission rates for microprolactinomas compared to macroprolactinomas, and adenomas that are enclosed within the gland may have a more favourable outcome compared with adenomas located at the lateral margins [29,54]. These findings have been endorsed in several systematic reviews and meta-analyses, which have reported TSS to deliver superior clinical outcomes compared to dopamine agonist therapy [19,20,63], with superior cost-effectiveness, although the absence of any randomised trials remains a major limitation . Interestingly, one systematic review specifically investigated prolactinoma patients undergoing surgery because of resistance or intolerance to dopamine agonists, or patient preference, and reported that 38% achieved sustained remission without further treatment (66% of microprolactinomas, 22% of macroprolactinomas), while 62% achieved remission with adjunctive dopamine agonist therapy .
As the majority of prolactinomas are microadenomas , selective and complete adenomectomy, which delivers long-term remission without causing additional pituitary deficits (and where possible correcting exisiting deficits), should be the goal of transsphenoidal surgery. This is particularly important for young women considering reproduction, who are the group most commonly affected by microprolactinomas. To facilitate selective adenomectomy, accurate preoperative localisation of the adenoma is important, to minimise the need for more extensive exploration of the gland, and thereby potentially reducing the risk of new pituitary deficiencies or other (e.g. neurovascular) complications. Nonetheless, even with advances in MR imaging, the detection of microadenomas, especially < 3 mm in maximum diameter, remains challenging . Additionally, the finding of an incidentaloma may confound management . In these situations, Met-PET may offer an additional route to confirming/revealing the tumor, as exemplified by the cases reported in our cohort, and also in other pituitary tumor subtypes [32, 33]. In this way, Met-PET complements routine clinical MRI to improve the accurate localization of small functioning tumours, and thereby enable patients who might otherwise not be considered suitable candidates for surgery or radiotherapy to progress to TSS or SRS.
Our findings are also consistent with previous reports that indicate microprolactinomas are particularly 11C-methionine-avid [41, 43]. Met-PET may therefore allow more reliable distinction between true microprolactinomas and coincidental small non-secretory adenomas, although formal studies would be required to confirm this. It is also likely that some patients with so-called “idiopathic hyperprolactinemia” harbor microadenomas that are beyond the resolution of current standard clinical MRI, and these may be identified by Met-PET.
An important limitation of this study is the small sample size. However, the cases reported here represent consecutive patients referred to our tertiary center over a four-year period and, importantly, all Met-PET scans demonstrated unequivocal findings. Although outcomes following TSS and SRS are only available for six patients, all demonstrated clinical and biochemical responses that confirm the accuracy of the PET. A further three patients are awaiting surgery (delayed by the pandemic), and the remaining four patients were all offered surgery. Accordingly, there was no selection bias when referring for surgery, and it seems unlikely that these patients would have fared less favorably at surgery given the comparable Met-PET findings. However, it will be important to reproduce our findings in larger cohorts in a mutlicenter study. Currently, the restricted availability of 11C-methionine (with its short half-life of 20 min) is an important limitation in making this technique more widely available [32,65], but several other centers in the UK and Europe have recently established molecular imaging for pituitary adenomas, including using related tracers [e.g. 18F-fluoroethyltyrosine (18F-FET)] and the establishment of a small number of centers in each country that develop appropriate expertise would be consistent with the broader Pituitary Tumor Centre Of Excellence (PTCOE) model .
In summary, when MRI appearances are indeterminate in a patient with a microprolactinoma, it is logical for surgeons and patients to be apprehensive about surgery, especially for a condition where pharmacological therapy has traditionally been considered as first line treatment. However, the findings reported here indicate that Met-PET, a non-invasive technique, can facilitate precise localization of microprolactinomas, including when MRI findings are inconclusive, thereby enabling the surgeon to represent the benefits and risks of surgery more accurately.