Reappraising the Role of Trans-Sphenoidal Surgery in Prolactin-Secreting Pituitary Tumors

Pier Paolo Mattogno (  pierpaolo.mattogno@policlinicogemelli.it ) Policlinico A Gemelli: Policlinico Universitario Agostino Gemelli https://orcid.org/0000-0003-2857-9096 Quintino Giorgio D’Alessandris Policlinico A Gemelli: Policlinico Universitario Agostino Gemelli Sabrina Chiloiro University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Antonio Bianchi University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Antonella Giampietro University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Alfredo Pontecorvi University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Laura De Marinis University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Alessandro Olivi University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Carmelo Anile University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli Liverana Lauretti University Hospital Agostino Gemelli: Policlinico Universitario Agostino Gemelli


Introduction
Pituitary adenomas, or pituitary neuroendocrine tumors (WHO 2017), account for 10% to 15% of primary intracranial neoplasms. Among secreting pituitary tumors, prolactinomas are the most common (40-50% of total) [1]. Prolactinomas, with their various biological and clinical features, might represent an oncological and neurosurgical challenge. Dopamine agonists (DA) are considered as rst-line treatment due to their e cacy and safety pro le, [2,3] while trans-sphenoidal surgery (TSS) has been con ned to failure of medical therapy, pituitary apoplexy with neurological worsening, and prolactinomas with wide cystic component. [4]. However, data on de nitive cure with DA are debated, [2,4] and many patients remain on life-long therapy to avoid disease relapse. On the other hand, several papers report good results with TSS as rst-line therapy for prolactinomas [5][6][7][8]. Moreover, the recent technical innovations introduced in TSS, such as high-de nition surgical endoscopes and extremely reliable neuronavigation systems, have made possible to further expand the surgical possibilities and to obtain better results as complete tumor resection with lower complication rates. [9] Thus, in the neurooncological/endocrinological community, a debate on the possibility to expand the traditional indications of TSS as rst-line treatment for prolactinomas is alive. [10,11] In the present study, we conducted a thorough analysis of our surgical and medical experience of over 25 years in the treatment of prolactinomas with the aim to verify the role of surgery.

Study Design
We conducted a retrospective and cross-sectional study, reviewing the clinical, radiological and surgical charts of consecutive patients enrolled according to the following inclusion criteria: 1) Diagnosis of prolactinoma; 2) Treatment with DA (cabergoline or bromocriptine) or/and with neurosurgical operation via TSS (either endonasal endoscopic or sublabial microsurgical); 3) Diagnosis and treatment of prolactinomas conducted at our Institution between January 1st, 1992 and December 31, 2016.
Were excluded from the study: 1) Patients carrying giant prolactinomas (diameter > 4 cm); 2) Patients with a follow-up shorter than 12 months.
All the patients provided the informed consent agreeing to research principles of Institutional Ethics Committee.

Clinical management of patients
For each patient, diagnosis of prolactinoma was made following the international guidelines [4]. All patients diagnosed having a prolactinoma were evaluated by a multidisciplinary team with a neuroendocrinologist and a neurosurgeon. According to Klibanski [12], TSS was offered as rst line treatment in case of pituitary apoplexy, and macroprolactinomas in patients with a psychiatric disorder (for which dopamine agonists are contraindicated); contrarily to Klibansky, we recommended surgery as rst choice even in macroadenomas determining visual eld defects and in case of microadenomas in fertile women with a pregnancy desire. Each time, therapeutic strategy was jointly discussed between endocrinologists, neurosurgeons and the patient, considering risks and bene ts, with the nal choice based upon the patient's preference.

Follow-up
During the follow-up, all patients underwent: prolactin dosage, one and three months after pituitary surgery/start of DA therapy, and then every six months; pituitary MRI, three and six months after pituitary surgery/start of DA therapy, and then every year.
Outcome at the end of follow was classi ed as: 1) cured: in cases of regression of clinical symptoms, normalization of basal prolactin levels (below the gender-speci c normal upper limit) and absence of neuroradiological evidence of residual/recurrent tumor, after at least 12 months from neurosurgical treatment or DA discontinuation; 2) controlled disease: in cases with normal serum PRL concentration and stable neuroimaging, during DA therapy; 3) uncontrolled disease: in cases with high serum PRL concentration (above the gender-speci c normal upper limit) and/or tumor progression on neuroimaging, during DA therapy. Outcomes 2) and 3) were grouped into "not cured".

Statistical analysis
Continuous variables were expressed as mean (range), categorical variables as absolute and relative frequency. Comparison of continuous variables between groups was performed using the Mann-Whitney U test. Comparison of categorical variables was performed by chi-square statistic using the Fisher exact test when appropriate. A multivariate analysis model was built using logistic regression to calculate the Odds Ratio (OR) of cure, by adjusting for the following parameters: size of the adenoma, gender, surgical treatment in the course of clinical history, type of rst treatment, cavernous sinus invasion. A p<0.05 was considered signi cant. A ROC curve was built to assess the diagnostic accuracy for cure of post-operative serum prolactin; the value with the highest Youden index [sensitivity-(1-speci city)] was designed as best cut-off. StatView ver 5.0 software was used (SAS Institute, Cary, NC).

Patient Population
Among all patients treated for prolactinoma at our Institution in the study period, 259 (164 women and 95 men) ful lled the criteria for enrollment in the present study. Baseline characteristics of patients are detailed in Table 1. Sixtyfour % of female patients were affected by microadenomas, whereas the majority of male patients harbored a macroadenoma (78.9%; p<0.0001, Fisher exact test). Mean age was 35.2 years; females were signi cantly younger than males (p<0.0001, Mann-Whitney U test). Mean followup was 102.2 months (range, 12-438 months) and did not differ signi cantly between genders.
At last follow-up, 113 patients (43.6% of cases) were considered cured. The remaining 146 patients (56.4 %) were not cured, carrying either a controlled or an uncontrolled disease.

Impact of surgery as rst-line treatment
Surgery as rst-line treatment was offered to 45.9% of patients and detailed data are provided in Table 1.
Overall, surgery as rst-line treatment did not signi cantly impact on rate of cure (Table 2). Female patients harboring microadenoma built up the subgroup of patients taking the best advantage from surgery as rst therapy.

Impact of surgery as second-line treatment
About half of the patients initially treated with DA received surgery as second-line treatment due to intolerance or resistance to medical therapy. Thus, overall, 194 out of 259 patients (74.9%) were surgically treated during the study period. Surgery determined a signi cant increase in rate of cure than DA alone in the whole cohort (50% vs 24.6%, p=0.0005, Fisher Exact Test). As detailed in Table 2, female patients, particularly those harboring microadenoma, had still the best advantage from surgery. Contrarily, surgery was not bene cial in males in terms of cure rate.
Adjustment for other factors impacting the rate of cure We then aimed at assessing the other parameters which had an impact on nal rate of cure. Results are shown in Table 3. Females (p<0.001), patients carrying microadenomas (p=0.0057) and not-cavernous sinus invasive adenomas (Knosp 0-II vs III-IV, p=0.02) had a higher cure rate at the end of follow-up.
At multivariate analysis, surgery (either as rst or second-line), female sex and microadenoma emerged as independent prognosticator of cure at the end of follow-up (Table 3). Noteworthy, among these factors, surgery was the most signi cant (p<0.0001) and had the highest odds ratio for cure (5.1).

Validation of results in long follow-up patients
In order to validate the results on the positive role of surgery for cure in prolactinomas, we explored the results on those patients with follow-up of at least 5 years.
One hundred sixty-four patients met this criterion, 128 of which had undergone TSS (as rst-line or as second-line treatment). As shown in Table 4, TSS determined a signi cant increase in cure rate both at univariate (p=0.0042) and at multivariate analysis (p=0.0005), thus con rming our ndings.

Selection biases
Due to the non-randomized design of the study, surgery was not homogeneously distributed among subgroups. As shown in Table 1, TSS was more frequent in males than in females (both as rst-line treatment, p>0.0001, and during the disease course, p=0.0045) and in macroadenomas than in microadenomas (p<0.0001 both as rst-and second-line), whereas cavernous sinus invasion was homogeneously distributed among groups. The dosage of PRL conducted in fasting condition, in the morning of the rst day after surgery was signi cantly lower in cured vs not cured patients (p<0.0001, Mann-Whitney U test; Figure 1). The best cutoff was set at 37.5 ng/ml. Moreover, by applying a clinically relevant cut-off value of 10 ng/ml, 86.4% of patients with lower values vs 27.3% of patients with higher values resulted to be cured at the end of follow-up (p<0.0001, Fisher exact test).

Discussion
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 ndings 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 con rming 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 bene t by surgical removal of prolactinomas. In fact, we showed that female patients treated with rst-line surgery had the higher rate of cure, regardless of tumor dimension; among them, women harboring microadenoma were the subgroup mostly bene ting from surgery ( Table 2).
According to current guidelines [4], the rst-line therapeutic choice for prolactinoma is the medical therapy with DA, whereas surgery is usually con ned 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][17][18][19][20][21][22][23][24][25][26][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][31][32][33]. In fact, a very detailed pathological analysis may facilitate the identi cation of cases with high risk of recurrence and may orient towards a personalized therapy, in particular in cases of di cult 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][36][37][38][39][40][41][42][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 rst-line possible treatments for the management of prolactinomas in reference centers.

Declarations
Funding: No funding was received for this research.
Con ict of Interest: All authors certify that they have no a liations with or involvement in any organization or entity with any nancial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonnancial interest (such as personal or professional relationships, a liations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Ethical Approval: The study was approved by local ethics committee. The study was conducted according to the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed consent: Informed consent was obtained from all individual participants included in the study.