In this study, we investigated the role of TSS in the treatment of prolactinomas, reviewing our cohort of patients that had been managed with surgical and/or medical therapies, over a period of 25 years.
Our findings demonstrate that patients in which the adenoma was surgically removed had the highest probability of reaching the cure. In fact, in this cohort of patients, TSS acts as an independent positive prognostic factor for cure of prolactinomas, together with female gender and microadenoma. Notably, in patients with follow-up longer than 5 years, the only independent positive prognosticators for cure remained surgery and female sex, thus confirming our assumption. Moreover, the prognostic value of surgery was independent from timing, thus highlighting its role also when performed as a second-line treatment, after DA failure.
Notably, our results allow to identify a group of patients that may strongly benefit by surgical removal of prolactinomas. In fact, we showed that female patients treated with first-line surgery had the higher rate of cure, regardless of tumor dimension; among them, women harboring microadenoma were the subgroup mostly benefiting from surgery (Table 2).
According to current guidelines [4], the first-line therapeutic choice for prolactinoma is the medical therapy with DA, whereas surgery is usually confined to a complementary therapy for patients resistant to DA. However, recent studies have proved that a recurrence of prolactinoma may be observed in 20-77% of cases after the withdrawal of DA [13], matching with tumoral dimension, invasion of cavernous sinus, nadir prolactin value reached during DA treatment [14], persistence of tumoral residual disease and duration of treatment with DA [15].
Our evidences are in line with what published by high-volume centers [10,16-27]: TSS is linked to low surgical complications, and a remission rate of about 80% and 40% respectively for micro and macroprolactinomas. Consistently, Andereggen et al. [28] showed that at 10 years follow-up, the control of hyperprolactinaemia required DA-agonist therapy in 32% of patients who underwent primary surgical therapy and in 64% of patients who had primary medical therapy and that the primary surgical therapy is a protective factor for long-term treatment with DA.
Then, it has been suggested that surgical removal of the adenoma should be part of the patients counselling for the decision of the initial treatment, due to the low morbidity of this procedure, if performed by an experienced neurosurgeon [29]. In addition, the available of tumoral tissue may allow a detailed pathological analysis, for investigating both biomarkers of aggressiveness, as Ki67, p53, mitotic count, minichromosome maintenance 7 (MCM7) and estrogen receptors, and biomarkers of treatment response, as dopamine and somatostatin receptors [30-33]. In fact, a very detailed pathological analysis may facilitate the identification of cases with high risk of recurrence and may orient towards a personalized therapy, in particular in cases of difficult and aggressive prolactinomas [34].
The main limitation of our study are its retrospective design and the lack of randomization. The main selection biases were the prevalence of males and macroadenomas in surgical patients, probably due to visual disturbances as a reason for surgery. However, this study describes a real life scenario of a large and monocentric series of patients, managed at a historical pituitary unit with a long-standing commitment on research about prolactin in physiological and pathological conditions [35-43]. Moreover, multivariate analysis is expected to reduce biases. Another limitation is that, in this study, the complex endocrine syndrome induced by prolactinomas has not been analyzed: focusing on a few selected serological and neuro-radiological aspects of the illness was essential in order to reliably analyze a considerable number of patients with a long follow-up.
Among the strong points of the study, though collected in a 25-year timeframe, our monocentric series is highly homogeneous as concerns indications, treatment, and follow-up. To further reduce the confounding factors of our analysis, giant prolactinomas have been excluded, because in such invasive cases a multimodality treatment, including radiotherapy and life-long DA, is often required.
In conclusion, TSS may represent a valid alternative to DA therapy, particularly in females with microadenomas, as provides the highest chance to cure at long-term follow-up.
Concurringly with aforementioned reports, our experience prompts surgery among the first-line possible treatments for the management of prolactinomas in reference centers.