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

Results

Patient Characteristics on Presentation

Of the 56 patients in this study, 40 were female (71%) and 16 were male (29%) with an average patient age of 35.6 years at surgery (SD 13.3). Fifty-three patients (95%) underwent surgery at Keck Hospital of USC and 3 patients (5%) were operated on at Los Angeles County + USC Medical Center. Nineteen patients (34%) underwent endoscopic endonasal transsphenoidal resection and the other 37 (66%) underwent a microscopic endonasal transsphenoidal procedure. Common presenting symptoms included amenorrhea/oligomenorrhea (34 patients, 61%), galactorrhea (19 patients, 34%), headache (25 patients, 45%), visual loss (11 patients, 20%), decreased libido (11 patients, 20%), fatigue (8 patients, 14%), and dizziness (5 patients, 9%). Six patients (11%) had undergone prior transsphenoidal resection and 47 patients (84%) had prior DA treatment. Only 9 patients (16%) had received no treatment prior to surgery, either because of DA intolerance or a preference for surgery as a first-line treatment (Table 1). Mean preoperative prolactin levels in patients on a DA was 251.8 ng/mL (SD 522.2).

Preoperative Tumor Neuroimaging Characteristics

Maximal tumor diameter was available for 45 patients with a mean of 1.6 cm (SD 0.86). Forty were macroadenomas (73%) and 15 were microprolactinomas (27%), with 1 being a giant prolactinoma (> 4 cm). Twenty-four (43%) demonstrated suprasellar extension, 9 (16%) exhibited infrasellar extension into the sphenoid sinus, 1 (2%) extended to the clivus, and 20 (36%) invaded one or both of the cavernous sinuses. Fifteen prolactinomas (27%) were purely intrasellar (see Table 1).

Pituitary Adenoma Pathology and Immunostaining

All except 3 tumors in this study were classified as prolactinomas (53, 95%). Of the 3 patients whose tumors did not stain positively for prolactin, one was a very small microprolactinoma that was suctioned before pathology could be sent and 2 had tumors that were negative for all hormonal markers. In all 3 cases, patients had documented pretreatment prolactin levels greater than 200 ng/mL. In addition to prolactin (53, 95%), tumors also stained for adrenocorticotropin hormone (8, 14%), luteinizing hormone (6, 11%), growth hormone (6, 11%), follicle-stimulating hormone (3, 5%), and thyrotropin (2, 4%).

MIB-1 labeling index was performed in 21 cases (38%) demonstrating a mean of 2.43 (SD 1.47). Staining for p53 was performed in 12 cases (21%), with 6 prolactinomas staining positively (50%) and 6 staining negatively (50%). Neither MIB-1 labeling index nor p53 staining was correlated with hormonal remission.

Postoperative Complications

The majority of patients (45, 80%) experienced no postoperative complications. Three patients (5%) experienced cerebrospinal fluid leak, 2 of which required surgical repair and the other self-resolved. Three patients (5%) became hyponatremic, 4 (7%) had transient DI, 2 experienced epistaxis (4%), and 2 (4%) had meningitis (Table 2). No patients experienced permanent DI and no patient deaths occurred.

Surgical Outcomes

The mean neuroimaging follow-up time was 33.3 months (SD 36.2). Follow-up imaging was available for 51 patients (91%) and showed gross total resection (GTR) in 25 patients (49%) and subtotal resection (STR) in 26 patients (51%). Five patients (9%) experienced tumor progression after STR at a mean time of 41.3 months, and 3 patients (5%) had tumor recurrence after GTR at a mean time of 30.7 months (see Table 2).

Hormonal Outcomes

POD1 prolactin levels were available for 42 patients (75%) with a median of 10.2 ng/mL (interquartile range, 3.4–67.2 ng/mL). The mean clinical follow-up time for all patients was 39.4 months (SD 42.1) with a median prolactin level of 16.7 ng/mL (interquartile range, 9.1–60.4 ng/mL) in the 48 patients with available follow-up levels. Hormonal outcome data were available for all but one patient demonstrating biochemical control with or without adjuvant therapy in 35 patients (64%) and surgical cure (hormonal remission without postoperative DA therapy) in 25 patients (46%) (see Table 2). This amounted to surgical cure of 73% of microadenomas (11 of 15) and 36% of macroadenomas (14 of 39) and biochemical control of 87% of microadenomas (13 of 15) and 56% of macroadenomas (22 of 39). No significant differences in surgical cure or biochemical control were noted between patients undergoing microscopic vs endoscopic transsphenoidal resection.

Adjuvant Therapy

Adjuvant therapy in the patients who did not experience surgical cure consisted of DA therapy, SRS, additional surgery, or a combination of treatments. Fourteen patients (25%) were prescribed DA alone, 4 of whom (7%) exhibited biochemical remission. Five patients (9%) underwent SRS alone, 2 of whom (4%) experienced biochemical control. Five patients (9%) had combination DA therapy and SRS, 3 of whom exhibited hormonal remission. One patient (2%) had combination DA therapy and repeat surgical resection and continued to be in nonremission, and one patient (2%) achieved remission after combination DA therapy, SRS, and repeat resection (see Table 2). Four patients (7%) did not undergo adjuvant therapy in the follow-up period.

Differences Based on Patient Sex

Men were significantly older than women at the time of surgery (45.8 vs 31.6 years; 95% CI, −21.2 to −7.3; P < .001) and presented with larger tumors (2.2 cm vs 1.4 cm; 95% CI, −1.4 cm to −0.28 cm; P = .004). Additionally, men were less likely to undergo surgical cure (19% vs 57%, P = .011). There were no significant differences between patient sex and preoperative or POD1 prolactin levels, prolactinoma invasion characteristics, extent of resection (EOR), or rate of biochemical cure (Table 3).

Predictors of Surgical Cure

Male patients were less likely to remit from surgery alone (19% of men remitted vs 57% of women, P = .011). Additionally, patients with prior transsphenoidal surgery were less likely to experience surgical cure than those who had not (0% vs 51%, P = .018). There was an insignificant trend of lower mean preoperative prolactin levels in patients that experienced surgical cure (96.8 ng/mL vs 361 ng/mL; 95% CI, −4.8 ng/mL to 533 ng/mL; P = .054). Patients with smaller prolactinomas were more likely to achieve surgical cure (1.3 cm vs 1.9 cm; 95% CI, 0.064 cm to 1.1 cm; P = .013). Cavernous sinus invasion (CSI) was more common in the surgical failure group (57% vs 12% in surgical cure group, P = .001). There were no significant associations between surgical failure and suprasellar, infrasellar, clivus, or frontal lobe extension, although this may be because of limited sample size. POD1 prolactin level was also a significant predictor of surgical cure (95.5 ng/mL in the surgical failure group vs 4.7 ng/mL in the surgical cure group, 95% CI, 39 ng/mL to 142 ng/mL; P = .001). Specifically, we found a POD1 prolactin level greater than 7.6 ng/mL predicted nonsurgical cure with a sensitivity of 79% and a specificity of 77% (area under the curve = 0.89; 95% CI, 0.79 to 0.99; Figure 2). Patients who underwent GTR of their tumor were more likely to experience surgical cure than those who underwent STR (75% vs 8%, P < .001; Table 4).

Figure 2.

Receiver operating characteristic (ROC) curve demonstrating the ability of postoperative day 1 prolactin to predict need for adjuvant treatment in our patient population.

Predictors of Biochemical Control

Mean preoperative prolactin levels were higher in the nonbiochemical control group than the biochemical control (with or without adjuvant therapy) group (512 ng/mL vs 89 ng/mL; 95% CI, 23 ng/mL to 823 ng/mL; P = .032). Biochemical control was more likely to be achieved in patients with smaller prolactinomas (1.4 cm vs 2.0 cm; 95% CI, 0.02 cm to 1.1 cm; P = .042). POD1 prolactin levels were a significant prognosticator for biochemical control with or without adjuvant therapy (19 ng/mL in the biochemical control with or without adjuvant therapy group vs 125 ng/mL in the nonbiochemical control group; 95% CI, 25 ng/mL to 186 ng/mL; P = .014). Patients who had undergone prior transsphenoidal surgery were less likely to achieve biochemical control than those who had not (17% vs 69%, P = .011). Additionally, biochemical control was more likely to be achieved in patients who underwent GTR than those who underwent STR (88% vs 35%, P < .001). No significant differences were noted between biochemical control and patient sex or tumor invasion characteristics.

Patients who experienced biochemical control after adjuvant therapy were more likely to have lower preoperative prolactin levels (69 ng/mL vs 673 ng/mL; 95% CI, 48 ng/mL to 1159 ng/mL; P = .036) and have tumors that invaded the cavernous sinuses (81% vs 18%, P = .048). There were no differences in POD1 prolactin levels and biochemical control in patients who underwent additional treatment (see Table 4).

Systematic Review

The 19 articles in our systematic review included 1536 prolactinoma cases treated via surgical resection.[8,12,16–32] These studies identified tumor size (11 of 19)[8,16–19,21–23,25,29,31] preoperative prolactin levels (10 of 19)[8,12,16–18,21,22,24,25,31] postoperative prolactin levels (10 of 19)[12,19–24,26,28,29,32] prior treatment (9 of 19),[12,16,17,20,21,23,26,28] extrasellar invasion (7 of 19),[8,12,18,20,25,27,31] CSI (7 of 19)[12,16,18,19,23,28,29] and surgical approach (6 of 19)[18,19,22,25,28,32] as main predictors of postoperative hormonal remission. Other significant predictors included patient age (1 of 19)[8] sex (1 of 19)[8] cystic tumor (1 of 19)[16] infiltration into the dura (1 of 19)[8] tumor encasement by the pituitary gland (1 of 19)[30] and plurihormonal vs pure lactotroph adenoma on immunohistochemistry (1 of 19)[29] (Table 5). Pooled analyses were performed on available data.

Fourteen studies reported patient sex, demonstrating 761 men and 560 women. All but one study[30] reported patient age with mean ages ranging from 30 to 44 years and reported follow-up times in all but 2 studies[28,32] ranging from 3 to 196 months. While not every study clearly delineated the number of patients receiving each treatment, in the studies that reported numbers 788 patients received surgical resection alone, 433 underwent surgical resection and postoperative DA therapy, and 68 received surgery with adjuvant DA and radiotherapy. Overall, hormonal remission occurred in 780 (50.7%) out of 1536 cases. In studies that reported outcomes by treatment group, 256 of 646 patients (39.6%) remitted from surgery alone, 170 of 273 patients (62.3%) achieved remission from surgery and DA therapy, and 42 of 59 patients (71.2%) remitted after surgery, DA, and radiotherapy. Eleven patient mortalities were reported.

The 14 studies that reported prolactinoma size classification included 727 macroprolactinomas, 629 microprolactinomas, and 99 giant prolactinomas (> 40 mm).[8,12,16,17,19,21,22,24–26,28–31] In studies that reported outcomes by prolactinoma size, 422 of 629 patients with microprolactinomas (67%), 260 of 727 patients with macroprolactinomas (36%), and 19 of 99 patients with giant prolactinomas (19%) achieved hormonal remission.[8,12,16–19,21–26,28,31]

Six studies[12,16,18,21,24,32] reported their findings according to sex, with a total of 145 surgically treated prolactinoma patients in 104 men and 41 women (47.7% and 28.3%, respectively). A total of 73.1% of men and 61.0% of women achieved remission at long-term follow up.

CSI was investigated as a predictive factor of remission for surgically managed prolactinomas in 7 studies, with 3 providing details amenable for pooled analysis.[12,16,23] In these studies, there were 110 prolactinoma patients, 48.2% of whom had adenomas with CSI.

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