Cure and Hormonal Control After Prolactinoma Resection

Case Series and Systematic Review

Marisa C. Penn; Tyler Cardinal; Yanchen Zhang; Brittany Abt; Phillip A. Bonney; Patricia Lorenzo; Michelle Lin; Jack Rosner; Martin Weiss; Gabriel Zada; John D. Carmichael

Disclosures

J Endo Soc. 2021;5(10) 

In This Article

Discussion

We report a retrospective clinical analysis of our 2.5-decade experience with the surgical treatment of patients with prolactinomas, demonstrating surgical cure or biochemical control in a majority of patients. Surgical resection of prolactinomas is typically reserved for tumors refractory to DA therapy, patients who are unable to tolerate medical therapy, or for those who are seeking to improve chances of successful pregnancy. In concordance with this standard of practice, our study of 56 patients in large part consisted of patients who presented with invasive tumors after failure of DA therapy. Our findings suggest surgical intervention for prolactinoma should be recommended on a judicious basis, particularly when clinical predictors, such as smaller preoperative size and lower prolactin levels, support a favorable outcome of surgical cure or biochemical control. However, patients with large, highly invasive prolactinomas and prolactin levels greater than 500 ng/mL rarely benefit from surgical intervention unless it is for treatment of rapid neurological deterioration. Multimodal treatment with DA therapy and fractionated radiation therapy may offer better long-term tumor control in these patients without the need for invasive surgery. Importantly, we suggest a POD1 prolactin level greater than 7.6 ng/mL predicts a patient will not undergo biochemical control from surgical resection alone with a sensitivity of 79% and a specificity of 77%. In these patients, plans for adjuvant therapy can be made shortly after surgery to readily achieve biochemical control.

Our cohort consisted of patients of similar age and an average proportion of female patients compared to other surgical series; however, our patients had fewer microprolactinomas and more macroprolactinomas. Our surgical cure rates were comparable to the higher rates found in the current literature both for microprolactinomas and macroprolactinomas as was the overall rate of biochemical control we achieved with or without adjuvant therapy. The surgical complication rate and incidence of major morbidity and mortality were extremely low.

Presently, there remains a paucity of US studies investigating the role of transsphenoidal resection in achieving biochemical control in previously treatment-refractory prolactinomas. Our formal systematic review demonstrated studies have most commonly found tumor size, prolactin levels, and extrasellar invasion to be significant predictors of biochemical control after surgical intervention. Microprolactinomas were associated with better outcomes than macroprolactinomas and giant prolactinomas, and those with CSI were associated with poorer outcomes, suggesting size and invasion are predictors of success. Sex also played a significant role in patient outcomes, with men more likely to achieve biochemical control. Although DA therapy remains the primary treatment option for prolactinomas, our review suggests surgery is an effective adjuvant treatment to DA therapy in carefully selected cases. A recent systematic review on the efficacy of surgical resection for prolactinoma treatment demonstrated biochemical control in up to 81% of patients and surgical cure in up to 67% of patients.[33] Unlike our systematic review, Zamanipoor Najafabadi et al did not assess predictors of remission and focused solely on the success of transsphenoidal resection in the literature.[33]

In contrast to the findings of our systematic review, we found prior surgical resection, tumor size, preoperative and POD1 prolactin levels, and EOR, but not tumor invasiveness or patient sex, significantly predicted postoperative biochemical control. Although predictors of surgical cure were similar, there were some key differences. Specifically, preoperative prolactin levels were not significantly associated with surgical cure, whereas patient sex and tumor invasiveness were. These findings are likely explained in part by the significant role EOR plays in surgical cure. Larger and more invasive tumors, especially those tumors invading the cavernous sinuses, are more difficult to fully resect. In our study male patients had larger tumors, and although there was not a significant difference between EOR and patient sex, men may have had more advanced disease that was less amenable to cure via surgical resection alone. Additional investigation is merited to determine whether sex is an independent predictor for failure to achieve surgical cure or if other factors influence outcomes in male prolactinoma patients. With adjuvant therapy, the outcome disparity between sexes was eliminated in our patients. Our finding that preoperative prolactin levels were not significantly associated with surgical cure but were associated with biochemical control may be a factor of limited sample size.

No patients in our study with preoperative prolactin above 500 ng/mL achieved surgical cure, and no patients with preoperative prolactin levels greater than 1000 ng/mL remitted irrespective of adjuvant therapy. Importantly, patients who eventually exhibited biochemical control after adjuvant therapy had lower preoperative prolactin levels and were more likely to have tumors that invaded the cavernous sinuses. This latter finding is likely indicative of a more aggressive adjuvant therapy strategy in patients with known residual tumor in the cavernous sinuses that leads to improved disease control. In patients in whom prolactin normalization is not expected, goals of surgical treatment include tumor control and/or reduction in medication dose requirements.

An analysis comparing our male and female prolactinoma patients revealed differences consistent with the recent literature.[12,16,18,23,26,27] Men were more likely to be older and have larger tumors than their female counterparts. These differences in age likely result from differing surgical indications, whereby men undergo surgery because of DA resistance and symptoms of mass effect, whereas women are more frequently intolerant of DA or desire pregnancy.[34] However, despite the more progressed state of prolactinomas in men, no association was observed between sex and biochemical control rates in our study. Furthermore, despite having larger tumors with greater tumor symptomology, prolactinomas in men were not more likely to invade outside the sella than prolactinomas in women. This finding may be limited to patients who proceed to surgical resection. Alternatively, the large, noninvasive prolactinomas found in men may lack tumor markers that promote invasion. This finding differs from some prior studies that have suggested that sex plays a predictive role in biochemical control;[8,10] however, a recent systematic review of pituitary adenoma outcomes also concluded that sex did not play a significant role in postoperative remission.[35]

Limitations

This study is primarily limited by its retrospective nature and sample size. Additionally, our mean clinical and imaging follow-up times were complicated by multiple factors, including a transition to an EMR system with loss of original records and losing patients to follow-up. Owing to sample size, conclusions about the role of SRS and sites of tumor invasion other than the cavernous sinus (frontal lobe, clivus, suprasellar, infrasellar) in surgical cure and biochemical control were unable to be drawn. We suspect this may have additionally affected the lack of significance we noted between preoperative prolactin levels in patients who achieved surgical cure vs those who did not. Of note, 8 patients in our study were missing long-term follow-up prolactin levels. Biochemical control status for these 8 patients was made by review of clinical notes from board-certified endocrinologists and confirmed via follow-up phone call. Data from phone follow-up for these patients were patient reported and assessed for normalization of prolactin levels and presence of symptomatology.

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