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)

Abstract and Introduction

Abstract

Context: Surgical management of prolactinomas is an important treatment for patients intolerant of dopamine agonist therapy. However, predictors of postoperative outcomes remain unclear.

Object: While transsphenoidal surgical resection (TSSR) is important second-line therapy in prolactinoma patients, predictors of surgical cure and biochemical remission following TSSR remain sparse.

Methods: A retrospective review of prolactinoma patients undergoing TSSR at the USC Pituitary Center from 1995 to 2020 was conducted. Participants were categorized as surgical cure (normalization of serum prolactin without medical treatment), surgical noncure, biochemical control (prolactin normalization with or without adjuvant therapy), and nonbiochemical control. A systematic review of the outcomes of surgically managed prolactinomas was performed.

Results: The 40 female and 16 male participants had an average age of 35.6 years. Prior treatment included transsphenoidal resection (6, 11%) and dopamine agonist treatment (47, 84%). The 40 macroadenomas and 15 microadenomas exhibited suprasellar extension (24, 43%) and parasellar invasion (20, 36%). Fifteen (27%) were purely intrasellar. Gross total resection was achieved in 25 patients (45%) and subtotal in 26 (46%). Surgical cure was achieved in 25 patients (46%) and biochemical control in 35 (64%). Surgical cure was more likely in smaller, noninvasive tumors, those that were fully resected, and patients with lower preoperative (< 1000 ng/mL) and immediately postoperative (< 7.6 ng/mL) prolactin levels. Ten of 26 patients (38%) undergoing adjuvant therapy achieved biochemical control, which was less likely in men and those with higher preoperative prolactin or invasive tumors.

Conclusion: Surgical resection of prolactinomas is a safe procedure that, when offered judiciously, can achieve symptom and/or biochemical control in a majority of patients. A variety of predictors may be useful in advising patients on likelihood of postoperative remission.

Introduction

Prolactinomas are prolactin-secreting adenomas arising from lactotroph cells of the pituitary gland, and comprise approximately 40% of pituitary tumors.^[1] There are 2 predominant categories of symptoms with which prolactinoma patients present: those due to elevated prolactin and its inhibition of gonadotropin-releasing hormone and those due to tumor mass effect.^[2] An increase in prolactin secretion commonly results in reproductive and sexual dysfunction, including oligomenorrhea, galactorrhea, and amenorrhea in women and decreased libido in men.^[3] Symptoms of mass effect include headaches, vision loss, and hypopituitarism and are usually seen in patients with macroprolactinomas.^[3]

Standard of care for treatment of prolactinomas centers around dopamine agonist (DA) therapy, which in the majority of cases is remarkably effective.^[4,5] Surgical resection is usually reserved for patients who are intolerant or resistant to DA therapy, as well as for some women harboring tumors who are considering pregnancy.^[6] Prior studies have reported postsurgical biochemical control rates ranging between 50% and 93% for microprolactinomas and between 30% and 80% for macroprolactinomas^[7–13] with mean follow-up of 19.6 to 138 months.

Although the effectiveness of surgical resection as a second-line therapy for prolactinomas has been reported, predictors of surgical cure (hormonal remission without postoperative DA therapy) and biochemical control with or without adjuvant postoperative DA therapy have not been extensively studied.

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Table 1. Overview of presenting patient and tumor characteristics
Patient characteristic	No. (%)
Female	40 (71%)
Male	16 (29%)
Age at surgery, mean ± SD, y	35.6 ± 13.3
Mean clinical follow-up time, mo	39.4 ± 42.1
Mean neuroimaging follow-up time, mo	33.3 ± 36.2
Type of surgical resection
Endoscopic endonasal transsphenoidal	19 (34%)
Microscopic endonasal transsphenoidal	37 (66%)
Presenting symptoms
Amenorrhea/oligomenorrhea	34 (61%)
Galactorrhea	19 (34%)
Headache	25 (45%)
Visual loss	11 (20%)
Decreased libido	11 (20%)
Fatigue	8 (14%)
Dizziness	5 (9%)
Prior treatment
Prior DA therapy	47 (84%)
Prior transsphenoidal resection	6 (11%)
No prior treatment	9 (16%)
Neuroimaging characteristics
Maximal tumor diameter, cm	1.6 ± 0.86
Macroadenomas	40 (73%)
Microadenomas	15 (27%)
Giant prolactinoma	1 (2%)
Suprasellar extension	24 (43%)
Sphenoid sinus invasion	9 (16%)
Clival extension	1 (2%)
Cavernous sinus invasion	20 (36%)
Purely intrasellar	15 (27%)

Abbreviation: DA, dopamine agonist.

Table 2. Postoperative outcomes and adjuvant therapy
Postoperative complications	No. (%)
Transient DI	4 (7)
Hyponatremia	3 (5)
CSF leak	3 (5)
Epistaxis	2 (4)
Meningitis	2 (4)
Surgical outcomes
Gross total resection	25 (49)
Subtotal resection	26 (51)
Tumor progression	5 (9)
Tumor recurrence	3 (5)
Hormonal outcomes
Surgical cure	25 (46)
Biochemical control	35 (64)
Adjuvant therapy
DA therapy	14 (25)
SRS	5 (9)
DA therapy + SRS	5 (9)
DA therapy + additional resection	1 (2)
DA therapy + SRS + additional resection	1 (2)

Abbreviation: CSF, cerebrospinal fluid; DA, dopamine agonist; DI, diabetes insipidus; SRS, stereotactic radiosurgery.

Table 3. Comparison of male and female patients
	Male (n = 16)	Female (n = 40)	95% CI	P
Mean age at time of surgery, y	45.8	31.6	–21.2 to −7.3	< .001^a
Preoperative prolactin, ng/mL	307 ± 798	231 ± 388	–436 to 285	.675^a
Mean maximal tumor diameter, mm	2.2cm	1.4cm	–1.4 to −0.28	.004^a
Suprasellar extension	9 (56%)	23 (56%)	–	.932^b
Cavernous sinus invasion	8 (50%)	28 (70%)	–	.158^b
Purely intrasellar	13 (81%)	28 (70%)	–	.39^b
Postoperative d 1 prolactin	46 ± 76	62 ± 112	–55 to 87	.652^b
Gross total resection	5 (31%)	20 (50%)	–	.148^b
Surgical cure	3 (19%)	22 (57%)	–	.011^b
Biochemical control	8 (50%)	27 (68%)	–	.178^b

^aIndependent samples t test.
^bChi-square analysis 95% CI.

Table 4. Comparison of patients with and without surgical cure and patients with and without biochemical control
	Surgical cure (n = 25)	No surgical cure (n = 30)	P, 95% CI	Biochemical control (n = 35)	Nonbiochemical control (n = 20)	P, 95% CI
Sex	3 (12%) male, 22 (88%) female	13 (43%) male, 17 (57%) female	.011^b	8 (23%) male, 27 (77%) female	8 (40%) male, 12 (60%) female	.178^b
Mean age at surgery, y	33.3 ± 13	37.7 ± 13.6	.228^a, −2.8 to 11.7	36.3 ± 14	34.5 ± 12.7	.63^a, –9.4 to 5.8
Prior transsphenoidal resection	0 (0%)	6 (20%)	.018^b	1 (3%)	5 (25%)	.011^b
Mean preoperative prolactin level, ng/mL	96.7 ± 96.9	361 ± 658	.054^a, −4.8 to 533	89.3 ± 38.3	512 ± 776	.04^a,22.8 to 823
Mean postoperative d 1 prolactin level, ng/mL	4.7 ± 4.1	95.5 ± 122.5	.001^a, 39 to 143	19.3 ± 36.4	125 ± 144	.014^a,25 to 186
Maximal diameter, cm	1.3 ± 7.3	1.9 ± 9.2	.028^a, 0.064 to 1.1	1.4 ± 0.72	2.0 ± 1.1	.042^a,0.02 to 1.1
Suprasellar extension	8 (32%)	16 (53%)	.11^b	13 (37%)	11 (55%)	.20^b
Cavernous sinus invasion	3 (12%)	17 (57%)	.001^b	12 (34%)	8 (40%)	.67^b
Purely intrasellar	11 (44%)	3 (10%)	.004^b	11 (31%)	3 (15%)	.18^b
Gross total resection(n = 50)	18 (90%)	2 (10%)	< .001^b	21 (70%)	9 (30%)	< .001^b

^aIndependent samples t test.
^bChi-square analysis 95% CI.

Table 5. Systematic review of series reporting outcomes after surgical resection of prolactinomas
Study authors	No.	% Female	No. of patients achieving hormonal remission			Criteria for hormonal remission	Follow-up time, mo	Prognostic variables
Study authors	No.	% Female	Micro (%)	Macro (%)	All (%)	Criteria for hormonal remission	Follow-up time, mo	Prognostic variables
Ogiwara et al	5	60.00	5/5 (100%)	–	100%	Surgical w/chemical cure	Mean: 3	Preoperative prolactin levels, tumor size, cavernous sinus invasion, previous treatment, cystic nature
Képénékian et al	20	44.68	–	15/17 (88.24%)	75.00%	Surgical w/chemical cure	Mean: 196 ± 100	Preoperative baseline prolactin levels, tumor size, previous treatment
Shimon et al	8	11.11	–	4/8 (50.00%)	50.00%	Surgical w/chemical cure	Mean: 93.6 ± 61.2	Giant prolactinoma (tumor size), cavernous sinus invasion, extrasellar involvement, surgical approach, preoperative prolactin levels
Vale et al	13	61.54	1/1 (100.00%)	9/12 (75.00%)	76.92%	Surgical w/chemical cure	Mean: 48	Tumor size, cavernous sinus invasion, postoperative prolactin levels, previous treatment
Vroonen et al	56	60.98	–	–	32.14%	Surgical w/chemical cure	88.5	Extrasellar involvement, previous treatment, postoperative prolactin level
Tamasauskas et al	32	100	19/32 (59.38%)	–	59.38%	Surgical w/chemical cure	Median: 88.5	Tumor size, previous treatment, preoperative prolactin levels, postoperative prolactin levels, postoperative treatment
Sinha et al	122	41.28	10/12 (83.33%)	40/83 (48.19%)	77.05%	Surgical w/chemical cure	Mean: 50.4 ± 32.4	Tumor size, surgical approach, preoperative prolactin levels, postoperative prolactin levels
Qu et al	87	0	13/18 (72.22%)	24/69 (34.78%)	72.41%	Surgical w/chemical cure	Median: 45.0	Extrasellar involvement, cavernous sinus invasion, previous treatment, preoperative prolactin level, postoperative prolactin level
Yu et al	18	13.33	–	4/18 (22.22%)	22.22%	Surgical w/chemical cure	Mean: 31.7	Giant prolactinoma (tumor size), cavernous sinus invasion, preoperative medical treatment, surgical approach, postoperative prolactin levels
Asano et al	8	0	–	8/8 (100.00%)	100%	Surgical w/chemical cure	Mean: 42.48 ± 14.52	Preoperative prolactin levels, postoperative prolactin levels
Gökalp et al	550	28.36	200/311 (64.31%)	15/222 (6.76%)	38.74%	Surgical cure	Mean: 86.4	Tumor size, extrasellar involvement, surgical approach, preoperative baseline prolactin levels
Jho et al	5	80.00	–	–	40.00%	Surgical w/chemical cure	Not reported	Postoperative prolactin levels, surgical approach
Merola et al	49	75.40	24/25 (96.00%)	23/24 (95.83%)	91.84%	Surgical w/chemical cure	60	Postoperative prolactin levels, preoperative medical treatment
Zada et al	20	Not reported	–	–	40.00%	Surgical cure	Median: 16	Extrasellar involvement, preoperative medical treatment
Gsponer et al	52	77.48	16/25 (64.00%)	10/26 (38.46%)	46.15%	Surgical w/chemical cure	Not reported	Surgical approach, cavernous sinus invasion, preoperative medical treatment, postoperative prolactin levels
Zielinski et al	48	92	–	–	71%	Surgical w/chemical cure	84	Cavernous sinus invasion (Knosp score), tumor size, plurihormonal vs pure lactotroph adenomas, postoperative prolactin levels
Losa et al	120	77.5	46/59 (78%)	31/61 (50.8%)	64.2%	Surgical cure	Mean: 50.2 ± 3.0	Age, sex, preoperative prolactin levels, tumor size, extrasellar involvement, dural infiltration
Micko et al	60	83	–	–	67%	Surgical cure	Mean: 37	Tumor enclosed by pituitary gland or not
Kreutzer et al	212	63	47/56 (84.8%)	–	42.7%	Surgical cure	Mean: 19.6	Preoperative prolactin levels, tumor size, extrasellar involvement
Present study	56	71.0	11/15 (73%)	14/39 (36%)	46%	Surgical cure	Median: 39.4	Cavernous sinus invasion, postoperative d 1 prolactin levels, tumor size, sex, prior transsphenoidal resection, extent of resection
Present study	56	71.0	13/15 (87%)	22/39 (56%)	64%	Surgical w/chemical cure	Median: 39.4	Preoperative prolactin levels, postoperative d 1 prolactin levels, tumor size, prior transsphenoidal surgery, extent of resection, cavernous sinus invasion